A series of (2R)-2-ethylchromane-2-carboxylic acid derivatives were synthesized and evaluated for their PPARγ and PPARα agonist activities with the goal of discovering a novel dual agonist. A structure-activity relationship was developed that led to the identification of compound 48 as a potent, selective, and structurally novel PPARγ/α dual agonist. Compound 48 showed substantial antihyperglycemic and hypolipidemic effects in animal models of type 2 diabetes and dyslipidemia.
Brian Covello: Diabetes Research ProposalBrian Covello
Brian Covello's diabetes research proposal. Type 2 diabetes mellitus consists of an array of dysfunctions characterized by hyperglycemia and resulting from the combination of resistance to insulin action, inadequate insulin secretion, and excessive or inappropriate glucagon secretion.
Essential update: FDA approves subcutaneous albiglutide for management of DM2
The FDA has approved once-weekly injectable albiglutide (Tanzeum), a glucagonlike peptide 1 (GLP-1) receptor agonist, along with diet and exercise for the treatment of type 2 diabetes.[1, 2] This agent may be used either as monotherapy or in combination with metformin, glimepiride, pioglitazone, or insulin.
Albiglutide should not be used for the following[1, 2] :
Patients with type 1 diabetes
Patients with diabetic ketoacidosis
First-line therapy in patients who can’t be managed with diet and exercise
Patients who have a personal or family history of medullary thyroid carcinoma (MTC)
Patients who have multiple endocrine neoplasia syndrome type 2
The most common adverse reactions associated with albiglutide were nausea/diarrhea and injection-site reactions.
There will be a boxed warning on albiglutide’s labeling about thyroid C-cell tumors being observed in rodent studies with this class of drugs; it is currently unknown whether albiglutide causes these tumors in humans, including MTC.[1, 2] Moreover, the FDA is also requiring a number of postmarketing studies, including a pediatric trial; an MTC case registry (≥15 y); and a cardiovascular (CV)-outcomes trial in patients with a baseline high risk of CV disease.
Signs and symptoms
Many patients with type 2 diabetes are asymptomatic. Clinical manifestations include the following:
Classic symptoms: Polyuria, polydipsia, polyphagia, and weight loss
Blurred vision
Lower-extremity paresthesias
Yeast infections (eg, balanitis in men)
See Presentation for more detail.
Diagnosis
Diagnostic criteria by the American Diabetes Association (ADA) include the following[3] :
A fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or higher, or
A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT), or
A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis
Whether a hemoglobin A1c (HbA1c) level of 6.5% or higher should be a primary diagnostic criterion or an optional criterion remains a point of controversy.
Indications for diabetes screening in asymptomatic adults includes the following[4, 5] :
Sustained blood pressure >135/80 mm Hg
Overweight and 1 or more other risk factors for diabetes (eg, first-degree relative with diabetes, BP >140/90 mm Hg, and HDL < 35 mg/dL and/or triglyceride level >250 mg/dL)
ADA recommends screening at age 45 years in the absence of the above criteria
See Workup for more detail.
Activation of p53 mediated glycolytic inhibition-oxidative stressapoptosis pa...rkkoiri
This research paper examines how a novel ruthenium(II) complex containing 4-carboxy N-ethylbenzamide (Ru(II)-CNEB) activates the p53-mediated glycolytic inhibition-oxidative stress-apoptosis pathway in Dalton's lymphoma (DL) cells in vivo. The study finds that Ru(II)-CNEB decreases expression of the inducible form of 6-phosphofructo-2-kinase (iPFK2/PFKFB3), a key regulator of glycolysis in DL cells. It also activates superoxide dismutase but decreases catalase and glutathione peroxidase, imposing oxidative stress in DL cells. This is consistent with enhanced p
This document describes the total synthesis of bleomycin A2 and related compounds. Two total syntheses of bleomycin A2 are reported that use bleomycin demethyl A2 as a key intermediate. A synthesis of decarbamoyl bleomycin demethyl A2 is also described, which represents the first synthetic access to this bleomycin congener. Improved methods for synthesizing the carbohydrate moiety of bleomycin are explored. Synthetic bleomycin was shown to have the same biological activity and DNA cleavage selectivity as naturally occurring bleomycin.
NQO1, a cytosolic oxidoreductase, plays an important role in maintaining proper redox status and insulin secretion in pancreatic β-cells. The study found that in insulin-secreting cells and isolated rodent islets, overexpressing NQO1 decreased reactive oxygen species production from quinones and the NAD(P)H/NAD(P)+ ratio, while NQO1 knockout cells had increased reactive oxygen species formation. This suggests NQO1 protects β-cells from oxidative stress by facilitating the full, two-electron reduction of quinones.
This study synthesized a series of hydroxy-substituted chalcone oxime derivatives and evaluated their inhibitory effects on tyrosinase and melanin formation in mouse melanoma cells. Two compounds exhibited much stronger tyrosinase inhibition than the positive control kojic acid. Kinetic studies showed that these compounds act as competitive tyrosinase inhibitors by binding to the enzyme's active site. Both compounds inhibited tyrosinase activity and melanin production in mouse melanoma cells, suggesting their potential as skin lightening agents.
Drug and gene delivery vehicles are biocompatible devices that can carry therapeutic components in the body. Synthetic vehicles include block copolymers, liposomes, dendrimers, and magnetic nanoparticles. Block copolymers form micelles with hydrophobic cores that can encapsulate drugs. Liposomes are phospholipid vesicles that can encapsulate both hydrophilic and hydrophobic drugs. Dendrimers are nanoscale polymers that can be functionalized to target drugs. Magnetic nanoparticles can be used for drug delivery, hyperthermia cancer treatment, and as MRI contrast agents. These vehicles aim to improve drug bioavailability and targeting while decreasing toxicity.
Design and synthesis of novel protein kinase R (PKR) inhibitorssagiv weintraub
This document describes the design and synthesis of novel protein kinase R (PKR) inhibitors. Using computer-aided drug design tools, the authors designed 10 benzoimidazole derivatives as potential PKR inhibitors based on the known inhibitor C16. Two of the synthesized compounds were found to inhibit recombinant PKR in pharmacologically relevant concentrations. One of these compounds also showed anti-apoptotic properties. The novel inhibitors provide additional chemotypes for inhibiting the PKR pathway and developing future PKR-targeting drugs.
Tetrameric peptide purified from hydrolysates of biodiesel byproducts of nann...Van-Tinh Nguyen
The document describes a study that identified and characterized a peptide from biodiesel byproducts of the microalgae Nannochloropsis oculata that promotes osteoblast differentiation. Enzymatic hydrolysis of the byproducts yielded various peptides, and the alcalase hydrolysate exhibited the highest osteoblastic differentiation activity. Further purification using liquid chromatography identified a tetrameric peptide (MPDW, 529.2 Da). This peptide was found to promote osteoblast differentiation in human and murine cells by increasing markers of osteoblast phenotype and mineralization through activation of the MAPK and Smad signaling pathways.
Brian Covello: Diabetes Research ProposalBrian Covello
Brian Covello's diabetes research proposal. Type 2 diabetes mellitus consists of an array of dysfunctions characterized by hyperglycemia and resulting from the combination of resistance to insulin action, inadequate insulin secretion, and excessive or inappropriate glucagon secretion.
Essential update: FDA approves subcutaneous albiglutide for management of DM2
The FDA has approved once-weekly injectable albiglutide (Tanzeum), a glucagonlike peptide 1 (GLP-1) receptor agonist, along with diet and exercise for the treatment of type 2 diabetes.[1, 2] This agent may be used either as monotherapy or in combination with metformin, glimepiride, pioglitazone, or insulin.
Albiglutide should not be used for the following[1, 2] :
Patients with type 1 diabetes
Patients with diabetic ketoacidosis
First-line therapy in patients who can’t be managed with diet and exercise
Patients who have a personal or family history of medullary thyroid carcinoma (MTC)
Patients who have multiple endocrine neoplasia syndrome type 2
The most common adverse reactions associated with albiglutide were nausea/diarrhea and injection-site reactions.
There will be a boxed warning on albiglutide’s labeling about thyroid C-cell tumors being observed in rodent studies with this class of drugs; it is currently unknown whether albiglutide causes these tumors in humans, including MTC.[1, 2] Moreover, the FDA is also requiring a number of postmarketing studies, including a pediatric trial; an MTC case registry (≥15 y); and a cardiovascular (CV)-outcomes trial in patients with a baseline high risk of CV disease.
Signs and symptoms
Many patients with type 2 diabetes are asymptomatic. Clinical manifestations include the following:
Classic symptoms: Polyuria, polydipsia, polyphagia, and weight loss
Blurred vision
Lower-extremity paresthesias
Yeast infections (eg, balanitis in men)
See Presentation for more detail.
Diagnosis
Diagnostic criteria by the American Diabetes Association (ADA) include the following[3] :
A fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or higher, or
A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT), or
A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis
Whether a hemoglobin A1c (HbA1c) level of 6.5% or higher should be a primary diagnostic criterion or an optional criterion remains a point of controversy.
Indications for diabetes screening in asymptomatic adults includes the following[4, 5] :
Sustained blood pressure >135/80 mm Hg
Overweight and 1 or more other risk factors for diabetes (eg, first-degree relative with diabetes, BP >140/90 mm Hg, and HDL < 35 mg/dL and/or triglyceride level >250 mg/dL)
ADA recommends screening at age 45 years in the absence of the above criteria
See Workup for more detail.
Activation of p53 mediated glycolytic inhibition-oxidative stressapoptosis pa...rkkoiri
This research paper examines how a novel ruthenium(II) complex containing 4-carboxy N-ethylbenzamide (Ru(II)-CNEB) activates the p53-mediated glycolytic inhibition-oxidative stress-apoptosis pathway in Dalton's lymphoma (DL) cells in vivo. The study finds that Ru(II)-CNEB decreases expression of the inducible form of 6-phosphofructo-2-kinase (iPFK2/PFKFB3), a key regulator of glycolysis in DL cells. It also activates superoxide dismutase but decreases catalase and glutathione peroxidase, imposing oxidative stress in DL cells. This is consistent with enhanced p
This document describes the total synthesis of bleomycin A2 and related compounds. Two total syntheses of bleomycin A2 are reported that use bleomycin demethyl A2 as a key intermediate. A synthesis of decarbamoyl bleomycin demethyl A2 is also described, which represents the first synthetic access to this bleomycin congener. Improved methods for synthesizing the carbohydrate moiety of bleomycin are explored. Synthetic bleomycin was shown to have the same biological activity and DNA cleavage selectivity as naturally occurring bleomycin.
NQO1, a cytosolic oxidoreductase, plays an important role in maintaining proper redox status and insulin secretion in pancreatic β-cells. The study found that in insulin-secreting cells and isolated rodent islets, overexpressing NQO1 decreased reactive oxygen species production from quinones and the NAD(P)H/NAD(P)+ ratio, while NQO1 knockout cells had increased reactive oxygen species formation. This suggests NQO1 protects β-cells from oxidative stress by facilitating the full, two-electron reduction of quinones.
This study synthesized a series of hydroxy-substituted chalcone oxime derivatives and evaluated their inhibitory effects on tyrosinase and melanin formation in mouse melanoma cells. Two compounds exhibited much stronger tyrosinase inhibition than the positive control kojic acid. Kinetic studies showed that these compounds act as competitive tyrosinase inhibitors by binding to the enzyme's active site. Both compounds inhibited tyrosinase activity and melanin production in mouse melanoma cells, suggesting their potential as skin lightening agents.
Drug and gene delivery vehicles are biocompatible devices that can carry therapeutic components in the body. Synthetic vehicles include block copolymers, liposomes, dendrimers, and magnetic nanoparticles. Block copolymers form micelles with hydrophobic cores that can encapsulate drugs. Liposomes are phospholipid vesicles that can encapsulate both hydrophilic and hydrophobic drugs. Dendrimers are nanoscale polymers that can be functionalized to target drugs. Magnetic nanoparticles can be used for drug delivery, hyperthermia cancer treatment, and as MRI contrast agents. These vehicles aim to improve drug bioavailability and targeting while decreasing toxicity.
Design and synthesis of novel protein kinase R (PKR) inhibitorssagiv weintraub
This document describes the design and synthesis of novel protein kinase R (PKR) inhibitors. Using computer-aided drug design tools, the authors designed 10 benzoimidazole derivatives as potential PKR inhibitors based on the known inhibitor C16. Two of the synthesized compounds were found to inhibit recombinant PKR in pharmacologically relevant concentrations. One of these compounds also showed anti-apoptotic properties. The novel inhibitors provide additional chemotypes for inhibiting the PKR pathway and developing future PKR-targeting drugs.
Tetrameric peptide purified from hydrolysates of biodiesel byproducts of nann...Van-Tinh Nguyen
The document describes a study that identified and characterized a peptide from biodiesel byproducts of the microalgae Nannochloropsis oculata that promotes osteoblast differentiation. Enzymatic hydrolysis of the byproducts yielded various peptides, and the alcalase hydrolysate exhibited the highest osteoblastic differentiation activity. Further purification using liquid chromatography identified a tetrameric peptide (MPDW, 529.2 Da). This peptide was found to promote osteoblast differentiation in human and murine cells by increasing markers of osteoblast phenotype and mineralization through activation of the MAPK and Smad signaling pathways.
Lactaptin, a peptide found in breast milk, has potential in cancer therapy. It induces apoptosis in cancer cells by activating caspases 3 and 7 and externalizing phosphatidylserine from the cell membrane. Lactaptin also inhibits the pro-cancer process of autophagy. Recombinant analogs of lactaptin like RL2 have been developed and shown to effectively induce apoptosis, suppress anti-apoptotic proteins, and inhibit tumor growth, demonstrating lactaptin's promise as a new molecule for anticancer drug development.
This document discusses stability problems and prevention strategies for proteins and peptides used in drug delivery systems. It describes how protein structure, including primary, secondary, tertiary, and quaternary levels can impact stability. Physical stability problems like denaturation from changes in solvent, pH, temperature and adsorption are explained. Chemical stability issues such as deamidation, oxidation, and reduction are also outlined. Methods to prevent various stability problems involving controlling solvents, pH, temperature, and use of stabilizing agents are presented.
Antihypertensive Peptides; Synthesis, Properties and Application in FoodsAkshay Ramani
1) Hypertension affects over 1 billion people worldwide and is a major cause of death and disability. Oxidative stress and inflammation contribute to hypertension and related conditions like cardiovascular disease.
2) Bioactive peptides derived from food proteins can regulate blood pressure by inhibiting the angiotensin converting enzyme (ACE). ACE is involved in blood pressure regulation and peptide inhibitors of ACE have potential for treating hypertension.
3) Bioactive peptides are released from proteins through enzymatic digestion and fermentation and have been shown to lower blood pressure in animal and human studies by inhibiting ACE.
A biopharmaceutical, also known as a biological medical product, biological, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semi synthesized from biological sources are called protein drugs.
Irreversible protein aggregation is problematic in the biotechnology industry, where aggregation is encountered throughout the lifetime of a therapeutic protein, including during refolding, purification, sterilization, shipping, and storage processes. The purpose of the current review is to provide a fundamental understanding of the mechanisms by which proteins aggregate and by which varying solution conditions, such as temperature, pH, salt type, salt concentration, cosolutes, preservatives, and surfactants, affect this process.
Stability studies of proteins and peptides.SULABH910
This document discusses stability studies of proteins and peptides. It covers both chemical and physical degradation mechanisms and factors that influence degradation rates. Chemical degradation includes deamidation, racemization, hydrolysis, disulfide formation, oxidation, and cross-linking. Physical degradation involves changes in structure like denaturation, aggregation, adsorption, and precipitation. Degradation rates depend on factors like pH, temperature, moisture content, and excipients. Kinetics are often first-order and follow Arrhenius behavior, allowing prediction of long-term stability from accelerated studies. Understanding degradation mechanisms is key to developing stable protein and peptide drug formulations.
This document discusses a study examining the effects of chicoric acid, caffeic acid, and chlorogenic acid on the bacterial virulence factor YopH and human CD45 phosphatase. Computational docking experiments showed that chicoric acid can bind to both the catalytic and secondary binding sites of YopH, while caffeic acid and chlorogenic acid only bind to the catalytic site. Experimental results demonstrated that chicoric acid treatment reduces the activity of recombinant YopH phosphatase from Yersinia enterocolitica and human CD45 phosphatase. The inhibition caused by chicoric acid was irreversible and did not induce oxidation of the catalytic cysteine residue.
Vitamins, coenzymes, and cofactors are organic or inorganic molecules that promote or catalyze biochemical reactions and metabolism. They can work with or be part of enzymes. Most cannot be synthesized by the human body and must come from dietary sources. They are involved in processes like carbohydrate, fat, and protein metabolism, cellular respiration, and synthesis of DNA, proteins, and other biomolecules. Deficiencies can cause disorders and diseases like beriberi, pellagra, anemia, and scurvy.
Vitamin E was discovered in 1922 and given its name in 1935. It is a fat-soluble vitamin that exists as both tocopherols and tocotrienols, with alpha-tocopherol being the most biologically active form. Vitamin E functions as a lipid-soluble antioxidant in the body, protecting cell membranes from oxidative damage by reacting with lipid peroxyl radicals. It is found naturally in many foods like sunflower seeds, avocados and olive oil. Vitamin E supports immune function, neurological health, and protects against heart disease and cancer. Deficiency can cause hemolytic anemia, neurological issues and retinal damage.
A curcuminoid is a linear diarylheptanoid molecules.
Curcuminoid have 3 derivatives curcumin, demethoxycurcumin & bisdemethoxycurcumin. These compounds are natural phenols and produce a pronounced yellow color. Due to less solubility curcumin derivatives are synthesized to increase their solubility and hence bioavailability. Curcuminoids are soluble in dimethyl sulfoxide (DMSO), acetone and ethanol but are poorly soluble in lipids. surfactants or co-surfactants used to increase solubility. Curcumin is mainly produced in industry as pigment by using turmeric oleoresin. After the isolation of the curcuminoids, the extract which is about 75% liquor mainly contains oil & resin. Curcumin is the strongest antioxidant, demethoxycurcumin the second strongest and bisdemethoxycurcumin the least effective The curcuminoids are capable of inhibiting damage to super coiled plasmid DNA by hydroxyl radicals. The derivatives of curcumin are good in trapping the 2,2-diphenyl-1 picrylhydrazyl(DPPH) radical. Curcumin is an active anti-cancer molecule against cancers of brain, breast, bones, blood, gastrointestinal tract, genitourinary tract, as well as thoracic and gynecological cancers.
It regulates numerous receptors, kinases, growth factors, transcriptional factors, and inflammatory cytokines.
It inhibits mammalian nuclear factor κappa B cell (NF-κB) by preventing its translocation to the nucleus. This inhibitory action upregulates the levels of preapoptotic and apoptotic cells, eliminating damaged cells, and discouraging abnormal growth patterns, as well as decreasing chemokine levels. Activated NF-κB is associated with oxidative stress, Inhibition of the nuclear factor by curcumin is consistent with the chemical’s role as an antioxidant. A homologous system to NF-κB signaling exists in plants Evidence that curcumin may play a similar role in C. longa as it does in humans. NF-κB is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet, irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection
1. The document discusses various topics related to proteins and peptides, including what proteins are, their properties, classification, metabolism, and some protein-related disorders.
2. Key points include that proteins are composed of amino acids and are essential for human life, occurring in all cells. They can be classified based on their structure as globular, fibrous or membrane proteins.
3. Protein metabolism involves breaking down proteins through catabolism and building new proteins through anabolism. The urea cycle is involved in detoxifying ammonia produced from amino acid catabolism.
4. Some protein-related disorders discussed are maple syrup urine disease, Gaucher disease, kwashiorkor, and
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
The document discusses crystal structures of phosphodiesterase 4 (PDE4) regulatory domains bound to small molecule inhibitors. It presents seven crystal structures that show the regulatory domain closed across the active site, revealing how PDE4 activity is regulated by controlling access to the active site. This structural insight allowed the authors to design PDE4 allosteric modulators that only partially inhibit cAMP hydrolysis, rather than completely inhibiting activity like existing drugs. The allosteric modulators showed reduced potential for side effects like emesis in cellular and animal studies while maintaining therapeutic effects.
Rapamycin was first discovered in 1970 on Easter Island. It is a potent immunosuppressant that prevents organ transplant rejection by inhibiting mTOR and IL-2, halting T-cell stimulation and the immune response. Rapamycin also has antitumor properties, as it inhibits cell growth and proliferation by blocking proteins involved in the cell cycle. It has a complex total synthesis and is used orally for immunosuppression after organ transplants, though it has many side effects.
Vitamins as coenzymes, different forms and deficiency disorders Lovnish Thakur
Vitamins are organic compounds which are needed in small quantities to sustain life.
Get from food, because the human body either does not produce enough of them, or none at all
Romidepsin is a natural product produced by fermentation that inhibits histone deacetylase (HDAC) enzymes, altering gene expression in cancer cells. It is metabolized to its active form which interacts with zinc ions in HDAC enzymes. This prevents cancer cell proliferation and induces apoptosis. Its synthesis involves multiple steps, including Mukaiyama aldol addition, ester hydrolysis, nucleophilic substitution, and disulphide bond formation.
use of omega-transaminase enzyme chemistry in the synthesis of JAK2 kinase in...Kashif Haider
use of enzyme chemistry is discussed with example of drugs in there synthesis. drugs in clinical trail of jak-2 enzyme inhibitors , and different scheme for enzyme synthesis is covered.
The interaction of Nrf2 and Glyoxalase I in response to lipid loading in Hepa...Farya Mubarik
This document summarizes a study that examined the interaction between Nrf2 and glyoxalase I in response to lipid loading in hepatocytes. The study first optimized the dose and duration of MG132 treatment, a proteasomal inhibitor, to induce accumulation of Nrf2 protein in HepG2 cells. It then examined the effects of oleic acid and palmitic acid on cell viability and found no significant effects. The study aims to determine if inhibition of proteasomal degradation leads to accumulation of Nrf2 and subsequent upregulation of glyoxalase I expression in response to lipid accumulation.
El documento describe cómo la innovación es fundamental para organizar eventos exitosos. Recomienda utilizar nuevas herramientas tecnológicas como conferencias virtuales, proyecciones de alta calidad y realidad aumentada para atraer a más público y clientes. También enfatiza la importancia de definir claramente los objetivos del evento para diferenciarse de la competencia y lograr una amplia cobertura en medios que genere recordación de la marca.
The document discusses how to identify and develop "monetizing patents" - patents that are commercially exploited and successfully monetized. It notes that while many patents are issued, only a small number achieve commercial success. Drawing an analogy to research on the traits of successful innovators, it suggests monetizing patents can be identified by their "DNA". This DNA includes solving important technological problems, providing unique customer value, actively participating in business ecosystems, and being legally savvy to obtain maximum rights. The document concludes by offering contact information for learning more about their methodology for identifying monetizing patents.
Lactaptin, a peptide found in breast milk, has potential in cancer therapy. It induces apoptosis in cancer cells by activating caspases 3 and 7 and externalizing phosphatidylserine from the cell membrane. Lactaptin also inhibits the pro-cancer process of autophagy. Recombinant analogs of lactaptin like RL2 have been developed and shown to effectively induce apoptosis, suppress anti-apoptotic proteins, and inhibit tumor growth, demonstrating lactaptin's promise as a new molecule for anticancer drug development.
This document discusses stability problems and prevention strategies for proteins and peptides used in drug delivery systems. It describes how protein structure, including primary, secondary, tertiary, and quaternary levels can impact stability. Physical stability problems like denaturation from changes in solvent, pH, temperature and adsorption are explained. Chemical stability issues such as deamidation, oxidation, and reduction are also outlined. Methods to prevent various stability problems involving controlling solvents, pH, temperature, and use of stabilizing agents are presented.
Antihypertensive Peptides; Synthesis, Properties and Application in FoodsAkshay Ramani
1) Hypertension affects over 1 billion people worldwide and is a major cause of death and disability. Oxidative stress and inflammation contribute to hypertension and related conditions like cardiovascular disease.
2) Bioactive peptides derived from food proteins can regulate blood pressure by inhibiting the angiotensin converting enzyme (ACE). ACE is involved in blood pressure regulation and peptide inhibitors of ACE have potential for treating hypertension.
3) Bioactive peptides are released from proteins through enzymatic digestion and fermentation and have been shown to lower blood pressure in animal and human studies by inhibiting ACE.
A biopharmaceutical, also known as a biological medical product, biological, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semi synthesized from biological sources are called protein drugs.
Irreversible protein aggregation is problematic in the biotechnology industry, where aggregation is encountered throughout the lifetime of a therapeutic protein, including during refolding, purification, sterilization, shipping, and storage processes. The purpose of the current review is to provide a fundamental understanding of the mechanisms by which proteins aggregate and by which varying solution conditions, such as temperature, pH, salt type, salt concentration, cosolutes, preservatives, and surfactants, affect this process.
Stability studies of proteins and peptides.SULABH910
This document discusses stability studies of proteins and peptides. It covers both chemical and physical degradation mechanisms and factors that influence degradation rates. Chemical degradation includes deamidation, racemization, hydrolysis, disulfide formation, oxidation, and cross-linking. Physical degradation involves changes in structure like denaturation, aggregation, adsorption, and precipitation. Degradation rates depend on factors like pH, temperature, moisture content, and excipients. Kinetics are often first-order and follow Arrhenius behavior, allowing prediction of long-term stability from accelerated studies. Understanding degradation mechanisms is key to developing stable protein and peptide drug formulations.
This document discusses a study examining the effects of chicoric acid, caffeic acid, and chlorogenic acid on the bacterial virulence factor YopH and human CD45 phosphatase. Computational docking experiments showed that chicoric acid can bind to both the catalytic and secondary binding sites of YopH, while caffeic acid and chlorogenic acid only bind to the catalytic site. Experimental results demonstrated that chicoric acid treatment reduces the activity of recombinant YopH phosphatase from Yersinia enterocolitica and human CD45 phosphatase. The inhibition caused by chicoric acid was irreversible and did not induce oxidation of the catalytic cysteine residue.
Vitamins, coenzymes, and cofactors are organic or inorganic molecules that promote or catalyze biochemical reactions and metabolism. They can work with or be part of enzymes. Most cannot be synthesized by the human body and must come from dietary sources. They are involved in processes like carbohydrate, fat, and protein metabolism, cellular respiration, and synthesis of DNA, proteins, and other biomolecules. Deficiencies can cause disorders and diseases like beriberi, pellagra, anemia, and scurvy.
Vitamin E was discovered in 1922 and given its name in 1935. It is a fat-soluble vitamin that exists as both tocopherols and tocotrienols, with alpha-tocopherol being the most biologically active form. Vitamin E functions as a lipid-soluble antioxidant in the body, protecting cell membranes from oxidative damage by reacting with lipid peroxyl radicals. It is found naturally in many foods like sunflower seeds, avocados and olive oil. Vitamin E supports immune function, neurological health, and protects against heart disease and cancer. Deficiency can cause hemolytic anemia, neurological issues and retinal damage.
A curcuminoid is a linear diarylheptanoid molecules.
Curcuminoid have 3 derivatives curcumin, demethoxycurcumin & bisdemethoxycurcumin. These compounds are natural phenols and produce a pronounced yellow color. Due to less solubility curcumin derivatives are synthesized to increase their solubility and hence bioavailability. Curcuminoids are soluble in dimethyl sulfoxide (DMSO), acetone and ethanol but are poorly soluble in lipids. surfactants or co-surfactants used to increase solubility. Curcumin is mainly produced in industry as pigment by using turmeric oleoresin. After the isolation of the curcuminoids, the extract which is about 75% liquor mainly contains oil & resin. Curcumin is the strongest antioxidant, demethoxycurcumin the second strongest and bisdemethoxycurcumin the least effective The curcuminoids are capable of inhibiting damage to super coiled plasmid DNA by hydroxyl radicals. The derivatives of curcumin are good in trapping the 2,2-diphenyl-1 picrylhydrazyl(DPPH) radical. Curcumin is an active anti-cancer molecule against cancers of brain, breast, bones, blood, gastrointestinal tract, genitourinary tract, as well as thoracic and gynecological cancers.
It regulates numerous receptors, kinases, growth factors, transcriptional factors, and inflammatory cytokines.
It inhibits mammalian nuclear factor κappa B cell (NF-κB) by preventing its translocation to the nucleus. This inhibitory action upregulates the levels of preapoptotic and apoptotic cells, eliminating damaged cells, and discouraging abnormal growth patterns, as well as decreasing chemokine levels. Activated NF-κB is associated with oxidative stress, Inhibition of the nuclear factor by curcumin is consistent with the chemical’s role as an antioxidant. A homologous system to NF-κB signaling exists in plants Evidence that curcumin may play a similar role in C. longa as it does in humans. NF-κB is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet, irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection
1. The document discusses various topics related to proteins and peptides, including what proteins are, their properties, classification, metabolism, and some protein-related disorders.
2. Key points include that proteins are composed of amino acids and are essential for human life, occurring in all cells. They can be classified based on their structure as globular, fibrous or membrane proteins.
3. Protein metabolism involves breaking down proteins through catabolism and building new proteins through anabolism. The urea cycle is involved in detoxifying ammonia produced from amino acid catabolism.
4. Some protein-related disorders discussed are maple syrup urine disease, Gaucher disease, kwashiorkor, and
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
The document discusses crystal structures of phosphodiesterase 4 (PDE4) regulatory domains bound to small molecule inhibitors. It presents seven crystal structures that show the regulatory domain closed across the active site, revealing how PDE4 activity is regulated by controlling access to the active site. This structural insight allowed the authors to design PDE4 allosteric modulators that only partially inhibit cAMP hydrolysis, rather than completely inhibiting activity like existing drugs. The allosteric modulators showed reduced potential for side effects like emesis in cellular and animal studies while maintaining therapeutic effects.
Rapamycin was first discovered in 1970 on Easter Island. It is a potent immunosuppressant that prevents organ transplant rejection by inhibiting mTOR and IL-2, halting T-cell stimulation and the immune response. Rapamycin also has antitumor properties, as it inhibits cell growth and proliferation by blocking proteins involved in the cell cycle. It has a complex total synthesis and is used orally for immunosuppression after organ transplants, though it has many side effects.
Vitamins as coenzymes, different forms and deficiency disorders Lovnish Thakur
Vitamins are organic compounds which are needed in small quantities to sustain life.
Get from food, because the human body either does not produce enough of them, or none at all
Romidepsin is a natural product produced by fermentation that inhibits histone deacetylase (HDAC) enzymes, altering gene expression in cancer cells. It is metabolized to its active form which interacts with zinc ions in HDAC enzymes. This prevents cancer cell proliferation and induces apoptosis. Its synthesis involves multiple steps, including Mukaiyama aldol addition, ester hydrolysis, nucleophilic substitution, and disulphide bond formation.
use of omega-transaminase enzyme chemistry in the synthesis of JAK2 kinase in...Kashif Haider
use of enzyme chemistry is discussed with example of drugs in there synthesis. drugs in clinical trail of jak-2 enzyme inhibitors , and different scheme for enzyme synthesis is covered.
The interaction of Nrf2 and Glyoxalase I in response to lipid loading in Hepa...Farya Mubarik
This document summarizes a study that examined the interaction between Nrf2 and glyoxalase I in response to lipid loading in hepatocytes. The study first optimized the dose and duration of MG132 treatment, a proteasomal inhibitor, to induce accumulation of Nrf2 protein in HepG2 cells. It then examined the effects of oleic acid and palmitic acid on cell viability and found no significant effects. The study aims to determine if inhibition of proteasomal degradation leads to accumulation of Nrf2 and subsequent upregulation of glyoxalase I expression in response to lipid accumulation.
El documento describe cómo la innovación es fundamental para organizar eventos exitosos. Recomienda utilizar nuevas herramientas tecnológicas como conferencias virtuales, proyecciones de alta calidad y realidad aumentada para atraer a más público y clientes. También enfatiza la importancia de definir claramente los objetivos del evento para diferenciarse de la competencia y lograr una amplia cobertura en medios que genere recordación de la marca.
The document discusses how to identify and develop "monetizing patents" - patents that are commercially exploited and successfully monetized. It notes that while many patents are issued, only a small number achieve commercial success. Drawing an analogy to research on the traits of successful innovators, it suggests monetizing patents can be identified by their "DNA". This DNA includes solving important technological problems, providing unique customer value, actively participating in business ecosystems, and being legally savvy to obtain maximum rights. The document concludes by offering contact information for learning more about their methodology for identifying monetizing patents.
El documento describe el proceso natural de envejecimiento del cuerpo a lo largo del tiempo, en el que los órganos se desarrollan pero también se deterioran gradualmente. Explica también que la oxidación es un cambio químico donde los átomos pierden electrones y que puede ocurrir de forma lenta o rápida, liberando en este último caso gran cantidad de energía. Por último, presenta un experimento para observar la oxidación de una moneda de cobre al ponerla en contacto con vinagre.
IATEFL 2015 presentation - The World Is My ClassroomRichard Osborne
This document provides an overview of using excursion-based lessons to move language learning out of the classroom and into the real world. It discusses taking students on educational outings to places like museums, villages, and historic sites. The key aspects covered include:
- Preparing students with background information and activities before the excursion
- Conducting activities like scavenger hunts and presentations during the excursion
- Following up after with assignments to reinforce language learning
- Considering logistics of transportation, size of groups, and potential risks to plan excursions safely and effectively.
The document argues that excursions can make language learning more authentic and stimulate students more than traditional classroom lessons. It
El documento presenta un proyecto sobre cómo evitar la corrosión. Explica que las turbinas de aviones requieren protección especial para evitar desgaste y corrosión debido a las altas temperaturas. Los recubrimientos protegen partes metálicas expuestas a temperaturas de hasta 1000°C. También define la corrosión y detalla experimentos para observarla, como oxidar una moneda de cobre con vinagre o quemar limaduras metálicas.
The document discusses Java memory management and how it is divided into different areas - the stack space, heap space, and string pool. The stack space stores method calls and references to objects in heap space. The heap space stores all objects created during program execution. The string pool stores and interns string literals to save memory and improve performance during string comparisons. Examples are provided to illustrate how objects and primitives are passed in methods and how string interning works.
This document discusses multiple approaches to language teaching, including the multiple intelligences approach. It provides an overview of Howard Gardner's theory of multiple intelligences, which characterizes human intelligence as having eight dimensions. The document then discusses how the multiple intelligences approach can be applied to language teaching, including through the use of projects tailored to different intelligences and an emphasis on individualizing learning to students' strengths. Finally, it concludes that the multiple intelligences approach aims to recognize learner differences and develop instruction accordingly.
Este documento establece normas y orientaciones para el desarrollo del año escolar 2015 en la educación básica. Define ocho compromisos de gestión escolar que las instituciones educativas deben cumplir para garantizar la calidad educativa, entre los que se incluyen el progreso de los aprendizajes de los estudiantes, la retención estudiantil, el cumplimiento del calendario escolar y la implementación del plan anual de trabajo. Asimismo, provee indicadores para medir el cumplimiento de cada compromiso y orienta a las instancias
By M. Stanton Evans. Forty years ago this month, the mortal remains of Joseph R. McCarthy were laid to rest near Appleton, Wis., not far from the modest farm where he was born. His death apparently closed a raucous, controversial saga, one of the most bitter and brutal in our nation’s history, with McCarthy typecast as the villain. Events of recent years, however, suggest the final chapters of this astounding story have yet to be recorded.
Este documento describe la investigación en didáctica de la lengua y la literatura, la cual se enfoca en crear conocimiento para mejorar la enseñanza y el aprendizaje significativo de la lengua y la literatura. Se divide en tres modalidades teóricas y prácticas. También describe los métodos de investigación, como el experimental, cuasi-experimental y descriptivo, así como las líneas de investigación centradas en procesos, metodologías, contextos, creencias y contenidos. Finalmente, presenta un ejemplo de proyecto de investigación sobre estrategias
Tracking emerging diseases from space: Geoinformatics for human healthMarkus Neteler
European and other countries are at increasing risk for new or re-emerging vector-borne diseases. Among the top ten vector-borne diseases with greatest potential to affect European citizens are Dengue fever, Chikungunya, Hantavirus, and Crimean-Congo hemorrhagic fever. Despite the risk of disease transmission, many vectors like the Asian tiger mosquito or ticks are also a nuisance in daily life. The examination of disease vector spread and a better understanding of spatio-temporal patterns in disease transmission and diffusion is greatly facilitated by Geoinformatics. New methods including the use of high resolution time series from space in spatial models enable us to predict species invasion and survival, and to assess potential health risks. Geoinformatics is able to address the increasing challenge for human and veterinary public health not only in Europe, but across the globe, assisting decision makers and public health authorities to develop surveillance plans and vector control.
This document discusses P-glycoprotein (P-gp), an ATP-dependent efflux pump found in the cell membranes of many tissues. P-gp pumps many foreign substances, drugs, and toxins out of cells. It plays an important physiological role and contributes to multidrug resistance in cancer cells by transporting chemotherapy drugs out of the cells. The document outlines the structure, mechanism of action, substrates, inhibitors, and approaches to bypassing P-gp efflux, such as using nanocarrier drug delivery systems.
Therapeutic Implications of Targeting Energy Metabolism in Breast CancerUniversity of Malaya
PPARs are ligand activated transcription factors. PPARγ agonists have been reported as a new and potentially efficacious treatment of inflammation, diabetes, obesity, cancer, AD, and schizophrenia. Since cancer cells show dysregulation of glycolysis they are potentially manageable through changes in metabolic environment. Interestingly, several of the genes involved in maintaining the metabolic environment and the central energy generation pathway are regulated or predicted to be regulated by PPARγ. The use of synthetic PPARγ ligands as drugs and their recent withdrawal/restricted usage highlight the lack of understanding of the molecular basis of these drugs, their off-target effects, and their network. These data further underscores the complexity of nuclear receptor signalling mechanisms. This paper will discuss the function and role of PPARγ in energy metabolism and cancer biology in general and its emergence as a promising therapeutic target in breast cancer.
The document describes the development of a multiplex panel to measure protein levels of HK2, PKM2, and LDHA in frozen tumor biopsies. Antibodies specific to these proteins were coupled to Luminex beads. Recombinant proteins were used to develop sandwich immunoassays and as calibrators. Sample handling procedures generated cytosolic and mitochondrial fractions from tumor tissues. The panel demonstrated proof-of-concept for monitoring PKM2 levels in cancer cell lines treated with PKM2 inhibitors in vitro.
Gold Standard Physiological Measurements and Novel Drug Delivery Methods - Se...InsideScientific
1. The document describes a presentation on investigating vitamin B12-conjugated PYY3-36 peptides for the treatment of obesity.
2. PYY3-36 is an intestinal hormone that reduces appetite, but has a short half-life. Conjugating it to vitamin B12 could improve its pharmacokinetics and pharmacodynamics when administered.
3. The presentation involves synthesizing B12-PYY3-36 conjugates, testing their receptor binding and activity in vitro, and evaluating their effects on food intake and body weight gain in rodent feeding studies after subcutaneous administration. The results suggest B12 conjugation enhances the appetite-suppressing effects of PYY3-36.
The document discusses anthracycline nano-delivery systems to overcome multiple drug resistance (MDR). It provides an overview of commonly used anthracycline drugs like doxorubicin and challenges with MDR. The review then summarizes over ten types of anthracycline nano-delivery systems that have been developed to overcome MDR, including liposomes, polymeric micelles, nanoparticles, conjugates, and carbon nanotubes. Several of these nano-delivery systems have advanced to clinical trials with the goal of improving cancer treatment by circumventing MDR.
This document summarizes a study that characterized the heme binding properties of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The key findings include:
1) GAPDH binds heme substoichiometrically, with one heme binding per GAPDH tetramer. The heme forms low-spin complexes with GAPDH that have distinct UV-visible absorption spectra depending on the heme redox state.
2) Kinetic analysis found heme binding to GAPDH is reversible and selective for heme structure. Heme binding affinity ranges from 19-390 nM depending on redox conditions.
3) Spectroscopic analysis indicates the heme in the GAPDH complex is bis-ligated by a histidine residue as the proximal
The document discusses the therapeutic uses of prostaglandins. It describes how prostaglandins are synthesized from arachidonic acid via various pathways, including the cyclooxygenase pathway which generates prostaglandins. Prostaglandins have various effects in the female reproductive system, with PGF2α and PGE2 promoting uterine contractions and cervical ripening, making prostaglandin analogs useful for inducing labor and abortions.
This document summarizes the development of a series of 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases (JNKs). A high-throughput screen identified an initial hit that was a moderately potent JNK1 inhibitor but was rapidly cleared in vitro. The authors synthesized analogs to reduce lipophilicity while maintaining or improving ligand efficiency. They synthesized over 50 compounds and tested them for JNK1 inhibition and cellular activity. The best compound showed improved properties over the initial hit, demonstrating that modifying the alkylamino portion can optimize JNK inhibition and pharmacokinetics.
This document describes the design, synthesis, and evaluation of a series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines as potential inhibitors of phosphodiesterase 4 (PDE4) and cancer cell growth. A ligand- and phase transfer catalyst-free intramolecular Heck reaction was used to synthesize the target compounds. Some compounds showed significant inhibition of PDE4B and growth inhibition of oral cancer cells in vitro. They also showed acceptable safety profiles in zebrafish embryos, but no apoptosis was observed. The goal was to develop PDE4 inhibitors that do not inhibit luciferase, which could produce false positives in assays.
This document describes the discovery of N-phenyl nicotinamides as potent inhibitors of Kdr, which is a receptor tyrosine kinase that plays a critical role in angiogenesis. A series of N-phenyl nicotinamides were synthesized and evaluated for their ability to inhibit Kdr. Compound 4, an unsubstituted nicotinamide, was found to be the most potent inhibitor with a Ki of 8 nM. Compound 4 showed efficacy in reducing tumor growth in mouse xenograft models. Cocrystallization studies provided insights into how these compounds bind to and stabilize an inactive conformation of Kdr. Overall, this work identified N-phenyl nicotinamides as a new class of potent
Keto reductases (AKRs) are overexpressed in a large number of human tumors and mediate
resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new agents in development may surmount this resistance by acting as specific AKR isoforms or AKR
pan-inhibitors to improve clinical outcome.
Keto reductases (AKRs) are overexpressed in a large number of human tumors and mediate
resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new
agents in development may surmount this resistance by acting as specific AKR isoforms or AKR
pan-inhibitors to improve clinical outcome.
Keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to
alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer
chemotherapeutic agents either because they are directly involved in their metabolism or help
eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid
peroxides). Furthermore, this cellular stress activates the nuclear factor-erythroid 2 p45-related
factor 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway. As many human AKR genes are
upregulated by the NRF2 transcription factor, this leads to a feed-forward mechanism to enhance
drug resistance. Resistance to major classes of chemotherapeutic agents (anthracyclines,
mitomycin, cis-platin, antitubulin agents, vinca alkaloids, and cyclophosphamide) occurs by this
mechanism. Human AKRs also catalyze the synthesis of androgens and estrogens and the
elimination of progestogens and are involved in hormonal-dependent malignancies. They are
upregulated by antihormonal therapy providing a second mechanism for cancer drug resistance.
Inhibitors of the NRF2 system or pan-AKR1C inhibitors offer promise to surmount cancer drug
resistance and/or synergize the effects of existing drugs.
The document discusses steroid hormones, their biosynthesis from cholesterol, and their classification. It describes that steroid hormones are synthesized in the adrenal cortex and secreted as mineralocorticoids like aldosterone, glucocorticoids like cortisol, and sex hormones. The document also discusses the roles of various steroid hormones, conditions like Cushing's syndrome and Addison's disease, and the use of steroids in treatment. It provides details on the enzymatic processes involved in steroid hormone synthesis and factors that influence their activities.
Gregory Carey's lab is interested in understanding redox biology and the mechanism of action of manumycin-A (Man-A), a natural antitumor compound. Specifically, they seek to determine how controlled changes in reactive oxygen species lead to dephosphorylation of critical targets like MEK and Akt, triggering apoptosis. They hypothesize that CDK2 and protein phosphatase 1 antagonism determines cell fate, and that Man-A may function as a CDK2 inhibitor or PP1 activator. Future work will investigate ROS sources, protein thioreactive sites, and potential Man-A adduction to proteins. The goal is to elucidate how damaged proteins are processed in response to ROS and kinases
This document discusses clopidogrel (Plavix) metabolism and response variability. It describes how CYP2C19 polymorphisms can affect clopidogrel's conversion to its active metabolite, leading to increased risk of therapeutic failure or adverse effects. It also discusses the drug interaction between clopidogrel and proton pump inhibitors like omeprazole, which inhibits CYP2C19 and reduces clopidogrel's efficacy through the same metabolic pathway. Healthcare providers should consider a patient's CYP2C19 genotype and avoid concurrent use of clopidogrel with omeprazole or other inhibitors when possible.
1. The study analyzed metabolic and lipid profiles of transgenic mice overexpressing CYP7A1, the rate-limiting enzyme in bile acid synthesis.
2. Lipidomics identified 7 lipid markers like lysophosphatidylcholines and sphingomyelins that were decreased in the transgenic mice when fed a high-fat diet.
3. Metabolomics identified 13 bile acid metabolites, including increased levels of tauro-β-muricholic acid, an antagonist of the farnesoid X receptor, in the intestine of transgenic mice.
4. The results suggest reducing 12α-hydroxylated bile acids and increasing intestinal tauro-β-muricholic acid may protect against
The aldo-keto reductase (AKR) superfamily consists of over150 protein members sharing
similar structure and enzymaticactivities. To date, 13 human AKRs have been identified,
andthey participate in xenobiotic detoxification, biosynthesis andmetabolism. Increasing
evidence suggests the involvement ofhuman AKR proteins in cancer development,
progressionand treatment. Some proteins demonstrate multiple function-al features in
addition to being a reductase for carbonylgroups. This review article discusses the most
recent progressmade in the study of humans AKRs.
International Journal of Clinical Pharmacology & Toxicology (IJCPT) ISSN:2167-910X is an Open Access journal, which aims to develop coherent means to modify drug therapy, with respect to the patient's genotype, and to ensure maximum efficiency with minimal contrary effects.
2. 1990s,15 a recent study revealed that fibrates are rather
nonselective PPAR agonists.10 Their beneficial effect on
lipids is considered to be mainly driven by the activation
of PPARR. PPARR is predominantly expressed in the
liver, where its activation results in enhanced lipid
uptake and catabolic metabolism. In a recent large
clinical trial, gemfibrozil treatment resulted in a 22%
decrease in CHD death and nonfatal myocardial infarc-
tion incidents among patients with coronary disease and
low HDLc levels (VA-HIT study).27,28 Also, fenofibrate
has been shown to reduce the progression of athero-
sclerosis and coronary events among patients with
diabetes.29
Considering the significantly increased risk of CHD
among patients with type 2 diabetes and the demon-
strated clinical beneficial effects of fibrates on lipid
profiles, we and others have postulated that a PPARR/γ
dual agonist might present a superior agent for the
treatment of type 2 diabetes and dyslipidemia.30-40 A
number of new chemical entities with PPARR/γ dual
activity are currently in preclinical and clinical studies.
A successful launch of the first agent of this class would
ultimately validate the concept of PPARR/γ dual activa-
tion for the treatment of hyperglycemia and dyslipi-
demia in type 2 diabetes.
Design Concept for the PPARr/γ Dual Agonists
As a class, glitazones have a chiral center at the
5-positon of the TZD ring. In the case of rosiglitazone,
it has been recently reported that only the (S)-enantio-
mer carries the PPAR activity and that the enantiomers
quickly racemize under physiological conditions.41,42 To
date, all glitazones have been developed as racemates.
Glitazones are generally PPARγ selective agonists.
Fibric acid (2-phenoxyisobutyric acid) is a common
substructure of fibrates. Gemfibrozil has a tris-homo
fibric acid moiety instead of fibric acid. Currently,
marketed fibrates are all achiral entities.
With this background, we set out to discover a potent
PPARR/γ dual agonist, which is chiral and structurally
distinct from glitazones. For the structural design, we
started from fibric acid. Thus, by forming a ring between
the phenyl group and the alkyl substituent R to the
carboxylate moiety, we conceived chromane-2-carboxylic
acid with a chiral center at the 2-position of the
chromane ring (Figure 1). We hoped that the PPARR
activities from the fibric acid moiety would be preserved
even after forming an extra ring. Given that TZD can
be viewed as a replacement of the carboxylic acid
moiety, it is interesting to note that the key functional
groups, namely, the acidic functional groups and the
phenyl group, are laid out in a very similar fashion in
both chromane-2-carboxylic acids and glitazones. On the
basis of this structural similarity, we assumed that it
would be possible to build PPARγ activity into the
chromane-2-carboxylic acid series. This “cyclized fibrate”
concept for generating chiral fibrates is not entirely new.
A few attempts have been reported since the 1970s, but
almost no improvement in the hypolipidemic activity
was observed.43,44 The scope of our structure-activity
relationship (SAR) studies is summarized in the struc-
ture in Table 1.
Chemistry
Compounds 3-10 were synthesized as described in
Scheme 1. An ether bond was formed between the 6- or
the 7-hydroxy-chromane-2-carboxylates (1a-d) shown
in Scheme 1 and the bromides (2a,b) using cesium
carbonate in dimethyl formamide (DMF) at 65 °C. The
resulting ester products were hydrolyzed to give the
desired carboxylic acids (3-10). Ethyl 6-hydroxychro-
mane-2-carboxylate (1a),45 ethyl 6-hydroxy-2-methyl-
chromane-2-carboxylate (1b),46 and ethyl 7-hydroxy-
chromane-2-carboxylate (1c)47 were prepared according
to the procedures reported in the literature. Compounds
1d and 11-13 were prepared from 1c through a
sequence of reactions: (i) protection of the phenol by a
benzyl group; (ii) standard ester enolate alkylation using
alkyl iodide and HMPA as a cosolvent; and (iii) depro-
tection of the benzyl group (Scheme 2).
Compounds 14-16 were prepared as described in
general Scheme 1 employing phenols 11-13. Com-
pounds 25-28 in Scheme 1 were synthesized from
Figure 1. Cyclized fibrate concept.
Scheme 1a
a Reagents: (i) Cs2CO3, DMF, 65 °C. (ii) 2N NaOH, iPrOH, 70
°C.
Scheme 2a
a Reagents: (i) Bzl-Br, K2CO3, acetone refluxed. (ii) Na-
HMDS, R-I, THF-HMPA, -78 °C. (iii) Pd/C, H2, EtOH.
3256 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 12 Koyama et al.
3. chromane carboxylate 11 and the bromides 21-24
(Scheme 3). Bromides 21-24 were prepared from known
phenols 17-20 by forming an ether bond with 1,3-
dibromopropane employing cesium carbonate (Scheme
3).48-50
Compounds 37-40 were synthesized from appropri-
ately substituted chromanes 1d and 11 and the bro-
mides 33-36 (Scheme 4), followed by ester hydrolysis.
Introduction of a halogen atom at the ortho position of
the phenols 29a,b was performed by electrophilic aro-
matic substitution reactions (Scheme 4). Upon treat-
ment with sulfuryl chloride in toluene at 70 °C, phe-
noxyphenol derivatives 29a,b gave the chloro-substituted
phenols 30 and 31. Introduction of a fluoro group to
phenol 29a was performed using 3,5-dichloro-1-fluoro-
pyridinium triflate, giving 32. These ortho halogen-
substituted phenols were reacted with 1,3-dibromopro-
pane, giving bromides 34-36. Bromide 33 was synthe-
sized from 29a reacting with 1,3-dibromopropane.
Chiral resolution of the intermediate 41 was ac-
complished by forming a covalent bond with the chiral
Table 1. In Vitro Human PPAR Activities of Chromane-2-carboxylic Acids
SPA IC50 (µM)a TA EC50 (µM)a
compd
phenol
position n R1 R2 R3 (R/S)b R δ γ R γ
3 6 1 H n-Pr H racemicc >15 >15 2.9 NAd 2.8
4 6 1 Me n-Pr H racemic 3.3 >50 1.7 NA 6.8
5 6 2 H n-Pr H racemic 5.8 >50 3.0 NA 2.5
6 6 2 Me n-Pr H racemic 2.0 >50 2.3 NA 1.2
7 7 1 H n-Pr H racemic 1.5 0.17 0.98 3.0 7.3
8 7 1 Me n-Pr H racemic 1.9 >50 0.75 0.1 1.0
9 7 2 H n-Pr H racemic >15 >15 1.8 6.3 1.6
10 7 2 Me n-Pr H racemic >15 >50 5.1 5.2 3.6
14 7 1 Et n-Pr H racemic 0.36 >50 0.44 0.03 1.0
15 7 1 n-Pr n-Pr H racemic 2.1 >50 0.37 0.12 0.83
16 7 1 i-Bu n-Pr H racemic 3.0 5.0 1.2 NTe NT
25 7 1 Et n-Pr F racemic 0.97 >50 1.2 0.01 0.75
26 7 1 Et n-Pr Cl racemic 4.0 >50 1.4 0.21 0.67
27 7 1 Et n-Pr OMe racemic >15 >50 0.63 4.6 0.89
28 7 1 Et n-Pr SO2Me racemic >15 >50 0.37 NA 2.8
37 7 1 Et H H racemic 1.7 >50 >15 0.22 10
38 7 1 Et F H racemic 0.37 >50 4.7 0.05 1.0
39 7 1 Et Cl H racemic 0.12 >15 0.69 0.03 0.16
40 7 1 Me Cl H racemic 0.12 >15 1.4 0.08 0.36
46 7 1 Et Cl H (R) 0.06 >15 0.25 0.01 0.08
47 7 1 Et Cl H (S) >15 >50 1.4 4.2 7.6
48 7 1 Et Cl F (R) 0.06 >15 0.26 0.04 0.17
49 7 1 Et Cl F (S) >15 >50 4.4 6.1 5.0
rosiglitazone >15 >50 0.2 NA 0.02
a Mean values are shown (n ) 3); SD ( 15%; SPA (scintillation proximity assay);51 TA (chimeric GAL4-hPPAR transactivation assay).52
b Absolute stereochemistry of the chiral center at the 2-position of the chromane ring. c Racemic mixture. d Not active: <20% activation
at 10 µM. e Not tested.
Scheme 3a
a Reagents: (i) Br(CH)3Br, Cs2CO3, DMF, 65 °C.
Scheme 4a
a Reagents: (i) SO2Cl2, diisobutylamine, toluene, 70 °C, or 3,5-
dichloro-1-fluoropyridinium triflate, CH2Cl2-CH3CN (9:1), 0 °C
to room temperature. (ii) Br(CH2)3Br, Cs2CO3, DMF, 65 °C. (iii)
Compounds 1d or 11, Cs2CO3, DMF, 65 °C. (iv) 2N NaOH, iPrOH,
70 °C.
PPARR/γ Antihyperglycemic and Hypolipidemic Agents Journal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3257
4. auxiliary (R)-pantolactone, which generated a pair of
chromatographically separable diastereomers (Scheme
5). The ethyl ester group of 41 was hydrolyzed to give
the corresponding carboxylic acid, which was esterified
with (R)-pantolactone using EDCI in dichloromethane
to give a mixture of the (R,R)-isomer 42 and the (R,S)-
isomer 43. These diastereomers were easily separated
by flash chromatography. We decided to determine the
absolute stereochemistry of the pantolactone-ester that
gave the more active final compounds. While this isomer
(which turned out to be 42 afterward) tended to remain
as an oil, replacement of its pantolactone moiety (R-
isomer) with the other enantiomer (S-pantolactone) gave
50 that was found to be highly crystalline (Scheme 5).
By using X-ray crystal analysis, the absolute stereo-
chemistry of the 2-position of the chromane ring of 50
was determined to be (R) relative to the known chiral
center of (S)-pantolactone. On the basis of this finding,
the absolute stereochemistries of 42-49 were assigned
as shown in Scheme 5. After the chiral resolution,
isomers 42 and 43 were individually hydrolyzed, esteri-
fied with diazomethane, and debenzylated to give
compounds 44 and 45, respectively. Chiral intermedi-
ates 44 and 45 were separately recrystallized from
dichloromethane/hexanes to yield prisms, which have
the same rotation value in opposite directions. Chiral
compounds 46-49 were synthesized starting from the
chiral intermediates 44 and 45 as described in Scheme
5.
Biology
In Vitro. Activities of compounds were evaluated for
both binding affinity and functional activity. First,
binding affinities for the PPARs were measured in a
scintillation proximity assay (SPA).51 Second, potencies
of PPAR gene activation were evaluated in cell-based
transcription assays using GAL4-PPAR chimeric recep-
tors.52 All results were produced in triplicate, and mean
values are reported. Generally, the SAR was directed
based on the results of these two in vitro assays.
Because the high binding affinity for the receptor did
not necessarily translate into significant functional
activity, the binding assay was mainly used as a
primary screen to exclude inactive compounds.
In Vivo. db/db Mouse Studies. db/db (leprdb-3J/
leprdb-3J) mice were used as a type 2 diabetic animal
model. Male db/db mice at 12-13 weeks of age and
nondiabetic db/+ (lean) mice from Jackson Laboratories
were housed seven mice per cage and fed a rodent chow
(Purina no. 5001) ad libitum with free access to water.
Mice (seven per group) received a once daily oral dosing
of test compounds with vehicle (0.25% methylcellulose)
by oral gavage for 11 days. The blood was collected from
the tail immediately prior to the next dosing at days 0,
4, 7, and 11 for measurement of the plasma glucose
levels.
Hamster Lipid Studies. Golden Syrian hamsters
weighing between 120 and 150 g were purchased from
Charles River Laboratories and used for the experi-
ments. Hamsters were housed in boxes (five per box)
and fed a normal rodent chow ad libitum with free
access to water. Hamsters (ten for each group) were
orally dosed with compounds (suspended in 0.5% me-
thylcellulose) for 9 days. On the morning of the 10th
day, hamsters were euthanized with carbon dioxide, and
blood samples were obtained via heart puncture. Serum
cholesterol and triglyceride levels were determined from
the samples.
Dog Lipid Studies. Mature male Beagle dogs weigh-
ing between 12 and 18 kg were purchased from Mar-
shall Farm, PA. They were housed individually and fed
a cholesterol-free chow diet ad libitum with free access
to water. Prior to starting experiments, the dogs (five
for each group) were bled weekly from the jugular vein
Scheme 5a
a Reagents: (i) 2N NaOH, iPrOH, 70 °C. (ii) (R)-Pantolactone, EDCI, CH2Cl2. (iii) Chromatographic separation. (iv) CH2N2. (v) 10%
Pd/C, H2, EtOH. (vi) Bromide 34 or 35, Cs2CO3, DMF, 65 °C. (vii) (S)-Pantolactone, EDCI, CH2Cl2.
3258 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 12 Koyama et al.
5. and their serum cholesterol levels were determined.
Test compounds were suspended in 0.5% methylcellu-
lose and gavaged daily to the dogs for 2 weeks. Blood
samples were taken during and after the dosing periods,
and serum cholesterol levels were determined.
Pharmacokinetic Studies. Male Sprague-Dawley
rats (n ) 3), male adult Beagle dogs (n ) 4), and male
adult Rhesus monkeys (n ) 3) that had been fasted
overnight received an oral gavage dose of 2 mg/kg, or
an intravenous dose of 0.5 mg/kg by bolus injection.
Blood samples were obtained from the femoral arterial
cannula for rat, the jugular vein for dog, and the
saphenous vein for monkey at designated time points
into heparin-containing tubes. The plasma was prepared
immediately by centrifugation, acidified by the addition
of 0.5 M formate buffer, pH 3.0, and stored at -70 °C.
Quantitative analysis was carried out with LC-MS/MS
using the PE Sciex API 3000 triplex quadruple mass
spectrometer.
Results and Discussion
Activities of compounds with human PPARs are
summarized in Table 1. Compounds 3-10 belong to the
initial set of compounds synthesized. The effects of
phenol linkage position, tether length, and R-substituent
were investigated. As for the effect of the phenol linkage
position, compounds with a 6-phenol linkage (3-6)
clearly lack in PPARR functional activity as seen in the
transactivation assay results. On the contrary, com-
pounds with a 7-phenol linkage (7-10) have both
PPARγ and PPARR activities, albeit not really potent.
For the tether length, the three-methylene tether (n )
1) seemed to give superior results as compared with the
four-methylene tether (n ) 2) on both PPARγ and
PPARR binding affinities (comparing compounds 7 and
9, 8 and 10). The effect of the R-substituent was not
clear from these data. It was quite encouraging that we
were able to see PPARR/γ dual activity from the very
first set of the compounds prepared. On the basis of
these findings, we decided to take compound 8 as a lead
and continue SAR studies with the 7-phenol linkage and
the three-methylene tether.
We then decided to investigate the effect of the
R-substituent more carefully. From the results of com-
pounds 7, 8, and 14-16, it became clear from the
binding affinity results that there is a desirable range
of size for the R-substituent. While methyl and ethyl
groups showed comparable levels of PPARγ activation,
the ethyl group gave superior PPARR activation. There-
fore, we decided to continue SAR studies primarily with
the ethyl group as the R-substituent.
Having optimized structural features for the left side
of the molecule, we then turned our attention to the
right side of the molecule and synthesized compounds
(25-28). We anticipated that the R3 position, para to
the oxygen substituent, might be metabolically vulner-
able. We assumed that it was prudent to block this
position with a substituent that is resistant to metabolic
oxidation. When compounds 14 and 25-28 were com-
pared, it appeared that the spacial requirement for this
position was rather critical; only hydrogen and fluoro
substituents seemed to be tolerated in order to maintain
potent PPARR activity. With respect to the PPARγ
activity, the effect of the R3 substituent did not seem to
be significant. In our previous series of PPAR agonists,
the propyl substituent at the R2 position has been
essential for the PPARγ activity.38,50-52 The effect of the
R2 group can be seen when compounds 14 and 37-39
and compounds 8 and 40 are compared. As the size of
the substituent increased, the PPARγ binding affinity
seemed to improve. However, as for the functional
activities, there seemed to be a desirable range of size
for the R2 group. The chlorine substituent at the R2
position gave consistently superior functional activity
for PPARγ as compared with the ones with the propyl
group at the R2 position (14 and 39 and 8 and 40). From
this study, it became clear that the chloro substituent
at the R2 position is optimal for both PPARγ and PPARR
functional activities.
Finally, we decided to examine the effect of chirality.
Chiral resolution was performed on our most potent
compound 39. Compounds 46 and 47 are the (R)- and
(S)-enantiomers of compound 39, respectively. Clearly,
the (R)-enantiomer carries far superior activity. Com-
pounds 48 and 49 were prepared as fluoro-substituted
analogues of 46 and 47 because of the potential me-
tabolism concern that was described earlier. Again, the
more active enantiomer has the (R)-stereochemistry.
Compound 48 showed no appreciable level of activity
in the human PPARδ transactivation assay (25% acti-
vation at 10 µM). Table 2 summarizes the pharmaco-
kinetic profiles of 46 and 48. In rat, compound 48 has a
significantly higher exposure (nAUC ) dose-normalized
AUC), lower clearance (Clp), and longer half-life (t1/2)
than compound 46. Although compound 46 has slightly
better in vitro activities than 48, we opted for 48 because
of its superior pharmacokinetic profile. Pharmacokinetic
profiles and in vitro PPAR activities of compound 48 in
other experimental animal species are listed in Tables
2 and 3. We were pleased to find that compound 48 has
desirable pharmacokinetic profiles and in vitro activities
also in dogs and rhesus monkeys.
Having optimized the in vitro activities, we then
decided to test our most potent compound in the db/db
mouse type 2 diabetes model. The db/db mouse is an
obese animal model of type 2 diabetes and is character-
ized by severe insulin resistance and marked hyper-
Table 2. Pharmacokinetic Profiles of 46 and 48
compd species route
dose
(mpk)
nAUCa,b
(µM h)
Clpa
(mL/min/kg)
t1/2
a
(h)
F
(%)
46 rat iv 0.5 5.6 ( 0.2 5.8 ( 0.2 1.2 ( 0.3
po 2.0 2.6 ( 1.4 43
48 rat iv 0.5 10 ( 1.9 3.4 ( 0.6 4.6 ( 0.8
po 2.0 4.8 ( 0.6 3.7 ( 0.7 48
dog iv 0.5 3.5 ( 1.2 10 ( 2.0
po 2.0 9.2 ( 4.3 92
monkey iv 0.5 8.6 ( 1.2 3.5 ( 1.7
po 2.0 1.7 ( 0.6 43
a Mean ( SD (n ) 3 for rat and monkey; n ) 4 for dog). b Dose-
normalized AUC.
Table 3. In Vitro Activity of 48 on PPARR and PPARγ of
Human and Preclinical Species
TA EC50 (µM)a
species R γ
mouse >3 0.15
hamster 0.02 0.2
dog 0.11 0.14
human 0.04 0.17
a Mean values (n ) 3) are shown; SD ( 15%.
PPARR/γ Antihyperglycemic and Hypolipidemic Agents Journal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3259
6. triglyceridemia. The in vivo antihyperglycemic activity
of 48 is depicted in Figure 2. Compound 48 exhibited
robust serum glucose level lowering in a dose-dependent
manner that was comparable to rosiglitazone. Antihy-
perglycemic activity of 48 in the db/db mouse is mainly
driven by its PPARγ activity because 48 does not have
significant activity on mouse PPARR. In addition, the
lipid-lowering activity of 48 was assessed in two animal
models: a Syrian hamster model and a dog model. The
results are summarized in Tables 4 and 5. In the
hamster model, compound 48 at 10 mpk caused com-
parable levels of cholesterol and triglyceride lowering
with fenofibrate treatment at 100 mpk. In the dog
studies, compound 48 achieved superior cholesterol
lowering to fenofibrate even at significantly lower doses.
Importantly, compound 48 was tested against other
nuclear receptors and was found to be inactive in GAL4
assays for the following receptors: no activation of
hLXRR, hLXRβ, RXR, or PXR at concentrations up to
10 µM. In addition, no binding to hERR, hERβ, FXR,
hTRβ, and hGR at concentrations up to 10 µM was
observed.
Conclusion
We have identified a series of structurally novel
antidiabetic (2R)-chromane-2-carboxylic acids as potent
PPARR/γ dual agonists. By combining the cyclized
fibrate concept and the side chains from our previous
studies, we were able to successfully incorporate both
PPARR and PPARγ activities into one structure. Sys-
tematic SAR studies directed toward selective PPARR/γ
dual agonism culminated in the discovery of compound
48, which exhibited comparable antihyperglycemic ac-
tivities to rosiglitazone in the db/db mouse type 2
diabetes animal model studies. In addition, the lipid-
lowering activities of compound 48 were amply demon-
strated in a Syrian hamster model and a dog model.
Unlike the currently marketed glitazone class of an-
tidiabetic drugs, compound 48 is a single enantiomer
that is not vulnerable to racemization. To date, the
clinical utility of PPARγ and PPARR agonists has been
proven separately by the glitazones and the fibrates,
respectively. However, the general strategy of treating
type 2 diabetes and dyslipidemia through the use of
PPARR/γ dual agonists and the ideal balance of PPARR
and PPARγ activities have yet to be validated in the
clinic. Compound 48 is one such PPARR/γ dual agonist
that could demonstrate the viability of this approach.
It is hoped that the PPARR/γ dual activation strategy
will provide a comprehensive treatment for type 2
diabetes and dyslipidemia.
Experimental Section
General. All commercial chemicals and solvents are reagent
grade and were used without further purification unless
otherwise specified. All reactions except those in aqueous
media were carried out under nitrogen atmosphere. Chro-
matographic purification was performed using flash chroma-
tography techniques and silica gel (E. Merck 230-400 mesh).
The following solvents were abbreviated: tetrahydrofuran
(THF), ethyl acetate (AcOEt), and methyl-tert-butyl-ether
(MTBE). 1
H NMR spectra were measured using Varian Unity
INOVA 500 MHz instrument. Chemical shifts were reported
in parts per million (ppm, δ units) using tetramethylsilane as
an internal standard. The mass spectrum was measured in
the positive ion mode using HP1100 and micromass ZMD
instruments (LC-MS system). Elemental analyses were ob-
tained from Robertson Microlit Laboratories (Madison, NJ).
General Procedure for the Synthesis of 3-10, 14-16,
25-28, and 37-40. To a DMF solution of ethyl-6 (or -7)-
hydroxy-chromane-carboxylate (1a-d or 11-13) (1.0 equiv)
and the bromide (2a,b, 21-24, or 33-36) (1.1 equiv) was
added cesium carbonate (1.2 equiv). The resulting suspension
was heated to 65 °C for 5 h. The reaction mixture was diluted
with MTBE and water. The organic layer was separated. The
aqueous layer was extracted twice with MTBE. The combined
organic layers were dried over anhydrous sodium sulfate,
filtered, concentrated under reduced pressure, and chromato-
graphed on silica gel eluting with a gradient mixture of AcOEt/
hexanes to give the corresponding ether product. This product
was dissolved in 2-propanol-2 N NaOH(aq) (3:1 v/v) and
heated to 70 °C overnight. After most of the solvent was
removed under reduced pressure, the residue was diluted with
AcOEt and 2 N HCl(aq). The organic layer was separated. The
aqueous layer was extracted twice with AcOEt. The combined
organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated to give the title compound (70-95%
yield).
6-{3-[2-Propyl-4-phenoxyphenoxy]propoxy}chromane-
2-carboxylic Acid (3). 1
H NMR (500 MHz, CD3OD): δ 7.27
(m, 2H), 7.01 (t, 1H, J ) 7.4 Hz), 6.89 (m, 3H), 6.77 (m, 3H),
6.69 (dd, 1H, J ) 2.8, J ) 8.8 Hz), 6.63 (d, 1H, J ) 2.8 Hz),
4.62 (m, 1H), 4.13 (m, 4H), 2.82 (m, 1H), 2.72 (m, 1H), 2.55
(m, 2H), 2.25 (m, 1H), 2.22 (p, 2H, J ) 6 Hz), 2.01 (m, 1H),
1.55 (sext, 2H, J ) 7.5), 0.89 (t, 3H, J ) 7.3). MS: m/e ) 463
(M + 1). Anal. (C28H30O6) C, H.
General Procedure of the Ester-Enolate Alkylation for
the Synthesis of (1d and 11-13). The synthesis of 11 is
described below. Compounds 1d, 12, and 13 were synthesized
Figure 2. In vivo activity of PPARR/γ dual agonist 48 in db/
db mice. Time course of antihyperglycemic activity. Lean mice
(n ) 7) and db/db mice (n ) 7) received a once daily dosing of
48 or rosiglitazone by oral gavage with vehicle. Blood glucose
levels were measured 24 h after dosing on the preceding day.
The figure plots the mean value ( SD.
Table 4. Effects of 48 on Serum Cholesterol and Triglyceride
in Hamster
treatment
dose
(mpk)
cholesterola
(mg/dL)
change
(%)
triglyceridea
(mg/dL)
change
(%)
vehicle 108 ( 5 305 ( 17
fenofibrate 100 67 ( 3 -38b 161 ( 4 -44b
48 3 85 ( 3 -21b 222 ( 18 -27b
48 10 65 ( 2 -40b 159 ( 9 -48b
a Mean ( SD (n ) 10). b p < 0.01 vs vehicle control.
Table 5. Effect of 48 on Serum Cholesterol in Doga
treatment dose (mpk) change (%)
fenofibrate 50 -16.3b
48 1 -23.3b
48 3 -31.6b
a Mean values are shown (n ) 5). b p < 0.05 vs vehicle control.
3260 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 12 Koyama et al.
7. following a similar procedure that employs the appropriate
alkyliodide instead of iodoethane in step B.
Ethyl 2-Ethyl-7-hydroxychromane-2-carboxylate (11).
Step A: Ethyl 7-Benzyloxychromane-2-carboxylate. To
a 5 L acetone solution of ethyl 7-hydroxy-chromane-2-carboxy-
late (630.1 g, 2.84 mol) were added potassium carbonate
powder (785 g, 5.68 mol) and benzyl bromide (405 mL, 3.41
mol). The resulting suspension was heated to reflux for 16 h.
The reaction mixture was filtered through a pad of Celite. The
filtrate was concentrated to give solid material, which was
redissolved in AcOEt, washed with water to remove residual
salt, dried over anhydrous magnesium sulfate, filtered, and
concentrated to a small volume. The addition of hexanes
caused precipitation of the title compound, which was collected
by suction-filtration. The filtrate was triturated from dichloro-
methane/hexanes to give more precipitates. Finally, the filtrate
was concentrated and then chromatographed on silica gel,
eluting with a gradient mixture of 20-80% dichloromethane/
hexanes. The combination of all of the crops yielded the title
compound 760.2 g as an off-white solid (86%). 1
H NMR (500
MHz, CDCl3): δ 7.33-7.46 (m, 5H), 6.96 (d, 1H), 6.621 (d, 1H),
6.58 (dd, 1H), 5.05 (s, 2H), 4.72 (q, 1H), 4.29 (q, 2H), 2.69-
2.84 (m, 2H), 2.29 (m, 1H), 2.21 (m, 1H), 1.33 (t, 3H).
Step B: Ethyl 7-Benzyloxy-2-ethylchromane-2-car-
boxylate. To a 320 mL anhydrous THF solution of ethyl
7-benzyloxychromane-2-carboxyate (14.6 g, 46.6 mmol) was
added hexamethylphosphoramide (distitilled from CaH2) (10.5
mL, 60.4 mmol). After the mixture was cooled in a dry ice-
acetone bath, sodium bis(trimethylsilyl)amide (1.0 M/THF)
(60.5 mL, 60.5 mmol) was added via syringe over a 15 min
period. The resulting orange solution was stirred at that
temperature for 30 min before iodoethane (18.6 mL, 233 mmol)
was added via syringe. The reaction was slowly warmed to
room temperature and stirred overnight. The solvent was
removed under reduced pressure, and the residue was diluted
with AcOEt and aqueous ammonium chloride (NH4Cl 7.2 g/200
mL water). The organic layer was separated, and the aqueous
layer was extracted with AcOEt twice. The combined organic
layers were dried over anhydrous sodium sulfate, filtered,
concentrated, and chromatographed on silica gel eluting with
7.5% AcOEt/hexanes to give the title compound 15.2 g (96%).
1
H NMR (500 MHz, CDCl3): δ 7.35 (m, 4H), 7.30 (m, 1H), 6.89
(d, 1H, J ) 8.3 Hz), 6.53 (d, 1H, J ) 2.6 Hz), 6.45 (dd, 1H, J
) 2.5 Hz, 8.2 Hz), 4.54 (s, 2H), 4.19 (m, 2H), 4.07 (m, 2H),
3.67 (t, 2H, J ) 6.3 Hz), 2.66-2.61 (m, 2H), 2.33 (m, 1H), 2.09
(p, 2H, J ) 6.2 Hz), 2.00 (m, 1H), 1.91 (m, 2H), 1.23 (t, 3H J
) 7.1 Hz), 1.04 (t, 3H, J ) 7.4 Hz). MS m/e ) 341 (M + 1).
Step C: Ethyl 7-Hydroxy-2-ethylchromane-2-carboxy-
late (11). To a 5 mL ethanol solution of ethyl 7-benzyloxy-2-
ethylchromane-2-carboxylate (228 mg, 0.67 mmol) were added
0.25 mL of water and 10 mg of 10% Pd/C. The resulting
suspension was placed in a Parr shaker and hydrogenated
under hydrogen atmosphere at 50 psi overnight. The reaction
suspension was then filtered through a pad of Celite, concen-
trated, and chromatographed on silica gel. Elution with a
gradient mixture of 20-30% AcOEt/hexanes gave the title
compound (166 mg, quant.) as a clear oil. 1
H NMR (500 MHz,
CDCl3): δ 6.87 (d, 1H, J ) 8 Hz), 6.47 (d, 1H, J ) 2.8 Hz),
6.38 (dd, 1H, J ) 2.8 Hz, 8 Hz), 4.99 (brs, 1H), 4.20 (m, 2H),
2.65 (m, 2H), 2.32 (m, 1H), 2.05-1.85 (m, 4H), 1.24 (t, 3H, J
) 7 Hz), 1.04 (t, 3H, J ) 7 Hz). MS m/e ) 251 (M + 1). Anal.
(C14H18O4) C, H.
General Procedure for the Synthesis of 21-24 and 33-
36. To a DMF solution (0.2 M based on the phenol) of the
phenol (17-20 and 30-32) (1.0 equiv) and 1,3-dibromopropane
(5.0 equiv) was added cesium carbonate (1.3 equiv). The
resulting suspension was heated to 65 °C overnight. The
reaction mixture was diluted with AcOEt and water. The
organic layer was separated. The aqueous layer was extracted
twice with AcOEt. The combined organic layers were dried
over anhydrous sodium sulfate, filtered, concentrated, and
chromatographed on silica gel. Elution with a gradient mixture
of AcOEt/hexanes or MTBE/hexanes yielded the title com-
pounds (yield 70-90%). Generally, the product contained a
small amount (5%) of an elimination product (3-[2-propyl-4-
phenoxyphenoxy]-1-propene).
3-[2-Propyl-4-(4-fluorophenoxy)phenoxy]-1-bromopro-
pane (21). 1
H NMR (500 MHz, CDCl3): δ 7.03-6.99 (m, 2H),
6.95-6.92 (m, 2H), 6.86-6.79 (m, 3H), 4.11 (t, 2H, J ) 5.8
Hz), 3.66 (t, 2H, J ) 5.8 Hz), 2.58 (t, 2H, J ) 7.8 Hz), 2.37 (q,
2H, J ) 5.8 Hz), 1.60 (m, 2H), 0.96 (t, 3H, J ) 7.3 Hz).
2-Chloro-4-phenoxyphenol (30). A 54 mL toluene solu-
tion of 4-phenoxyphenol (2.0 g, 107 mmol) and diisobutylamine
(0.15 mL, 0.86 mmol) was heated to 70 °C. To it was added
sulfuryl chloride (0.69 mL, 8.6 mmol) over 2 h. The reaction
mixture was stirred for 1 h after the addition was complete.
Then, the reaction mixture was concentrated and diluted in
AcOEt and saturated aqueous sodium bicarbonate solution.
The organic layer was separated. The aqueous layer was
extracted twice with AcOEt. The combined organic layer was
dried over anhydrous sodium sulfate, filtered, concentrated,
and chromatographed on silica gel. Elution with 15% AcOEt/
hexanes gave the title compound as a pale yellow syrup (2.3
g, 97%). 1
H NMR (500 MHz, CDCl3): δ 7.35 (m, 2H), 7.12 (m,
1H), 7.06 (d, 1H), 7.02 (d, 1H), 6.99 (d, 2H), 6.92 (dd, 1H), 5.69
(s, 1H). Anal. (C12H9O2Cl1) C, H, Cl.
2-Chloro-4-(4-fluorophenoxy)phenol (31). This com-
pound was prepared from 4-(4-fluorophenoxy)phenol according
to a procedure similar to the one used for the synthesis of
compound 30. 1
H NMR (500 MHz, CDCl3): δ 7.06-7.00 (m,
4H), 6.98-6.94 (m, 2H), 6.88 (app. q. 1H), 5.40 (s, 1H).
2-Fluoro-4-phenoxyphenol (32). To a 250 mL dichlo-
romethane solution of 4-phenoxyphenol (2.0 g, 10.7 mmol) was
added 3,5-dichloro-1-fluoro-pyridinium triflate (4.14 g, 13.1
mmol). After the mixture was heated to reflux for 1 h, the
solvent was removed. The residue was diluted with AcOEt and
saturated aqueous sodium bicarbonate solution. The organic
layer was separated, dried over anhydrous sodium sulfate,
filtered, concentrated, and chromatographed on silica gel.
Elution with 10% MTBE/hexanes gave 312 mg of the title
compound as a pale yellow oil. 1
H NMR (500 MHz, CDCl3): δ
7.34 (m, 2H), 7.11 (m, 1H), 6.98 (m, 3H), 6.82 (dd, 1H), 6.76
(m, 1H), 5.00 (s, 1H).
Optical Resolution of Ethyl 7-Benzyloxy-2-ethylchro-
mane-2-carboxylate (41). (2R)-Methyl 2-Ethyl-7-hydroxy-
chromane-2-carboxylate (44). Step A: 7-Benzyloxy-2-
ethylchromane-2-carboxylic Acid. To a 2 L 2-propanol
solution of ethyl 7-benzyloxy-2-ethylchromane-2-carboxylate
(41) (155 g, 0.455 mol) was added 1 L of aqueous 5 N sodium
hydroxide. This solution was heated to 70 °C overnight.
2-Propanol was removed under reduced pressure. The residue
was acidified with 300 mL of concentrated hydrochloric acid
and 2 N hydrochloric acid to pH 1. The acidic solution was
extracted three times with AcOEt. The combined organic
layers were dried over anhydrous sodium sulfate, filtered, and
concentrated to give a yellow oil, which crystallized upon
standing (130 g, 91%).
Step B: Resolution of the Racemate. (1) Ester Forma-
tion with (R)-Pantolactone. To a 1.1 L dichloromethane
solution of 7-benzyloxy-2-ethylchromane-2-carboxylic acid (75
g, 0.24 mol) and (R)-pantolactone (100 g, 0.768 mol) were added
EDCI (55.5 g, 0.289 mol) and 4-(dimethylamino)pyridine (6.4
g, 0.054 mol). This solution was stirred at room temperature
overnight. The solvent was removed under reduced pressure.
The residue was diluted with AcOEt, washed with water and
brine, dried over anhydrous magnesium sulfate, filtered, and
concentrated to give a yellow oil (137 g, crude).
(2) Chromatographic Separation of the Diastereo-
mers. The crude ester obtained as described above was
dissolved in hexanes and a small amount of dichloromethane
and then charged on a silica gel column. Elution with 10%
THF/hexanes (48 Ls), 12.5% THF/hexanes (64 Ls), and 25%
AcOEt/hexanes (4 Ls) gave the faster eluting 42 (R,R)-isomer
(30.4 g, 30%) as a thick colorless oil, the more slowly eluting
43 (R,S)-isomer (34.5 g, 34%) as a white solid, and a mixture
of the diastereomers (7 g, 7%) as a yellow oil.
Compound 42. (R,R)-Isomer. 1
H NMR (500 MHz,
CDCl3): δ 7.49 (m, 2H), 7.44 (m, 2H), 7.33 (m, 1H), 6.93 (d,
PPARR/γ Antihyperglycemic and Hypolipidemic Agents Journal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3261
8. 1H, J ) 8.5 Hz), 6.61 (d, 1H, J ) 2.5 Hz), 6.55 (dd, 1H, J )
2.6, 8.4 Hz), 5.35 (s, 1H), 5.05 (s, 2H), 4.00 (s, 2H), 2.75 (m,
2H), 2.45 (m, 1H), 2.10 (m, 1H), 1.95 (m, 2H), 1.31 (t, 3H, J )
7.5 Hz), 1.03 (s, 3H), 0.87 (s, 3H).
Compound 43. (R,S)-Isomer. 1
H NMR (500 MHz,
CDCl3): δ 7.44 (m, 2H), 7.39 (m, 2H), 7.33 (m, 1H), 6.93 (d,
1H, J ) 8.5 Hz), 6.59 (1H, J ) 2.5 Hz), 6.54 (dd, 1H, J ) 2.6,
8.4 Hz), 5.35 (s, 1H), 5.05 (s, 2H), 4.0 (s, 2H), 2.75 (m, 2H),
2.35 (m, 1H), 2.10 (m, 1H), 2.00 (m, 2H), 1.20 (s, 3H), 1.12 (t,
3H, J ) 7.5 Hz), 1.03 (s, 3H).
Step C: (2R)-Methyl 2-Ethyl-7-hydroxychromane-2-
carboxylate (44). To a 250 mL round-bottomed flask were
added the 42 (R,R) ester (5.07 g, 11.9 mmol) obtained as
described in step B, 50 mL of 2-propanol, and 50 mL of aqueous
2.5 N sodium hydroxide. This solution was heated to 65 °C
overnight. 2-Propanol was removed under reduced pressure.
The residue was acidified to pH 1 with 2 N hydrochloric acid
and then extracted with AcOEt three times. The combined
organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated to give a thick oil. This crude product
was dissolved in dichloromethane and treated with diazo-
methane ethereal solution. After the gas evolution ceased, the
solution was concentrated and the resulting oil was chromato-
graphed on silica gel. Elution with a gradient mixture of 10-
12.5% AcOEt/hexanes gave the corresponding methyl ester.
Then, the methyl ester was dissolved in 200 mL of ethanol
and 6 mL of water, combined with 200 mg of 10% Pd/C, placed
in a Parr shaker, and hydrogenated (H2, 50 psi) overnight. The
catalyst was removed by suction-filtration through a pad of
Celite. The filtrate was concentrated and chromatographed on
silica gel using gradient elution 20-30% AcOEt/hexanes to
give 2.75 g of the title compound (97%). Recrystallization from
dichloromethane/hexanes gave prisms; mp 98.0-98.5 °C. 1
H
NMR (500 MHz, CDCl3): δ 6.8 (d, 1H, J ) 8.2 Hz), 6.45 (d,
1H, J ) 2.6), 6.38 (dd, 1H, J ) 2.5, J ) 8.0 Hz), 3.73 (s, 3H),
2.59-2.66 (m, 2H), 2.33 (m, 1H), 1.99 (sext, 1H), 1.91 (m, 2H),
1.04 (t, 3H). MS: m/e ) 237 (M + 1). [R]D
20
+106.6 (c ) 1,
MeOH). Anal. (C13H16O4) C, H.
(2S)-Methyl 2-Ethyl-7-hydroxychromane-2-carboxy-
late (45). Following the same procedure as compound 44, the
title compound was synthesized from the 43 (R,S)-isomer.
Recrystallization from dichloromethane/hexanes gave prisms;
mp 98.0-98.5 °C. 1
H NMR (500 MHz, CDCl3): δ 6.8 (d, 1H, J
) 8.2 Hz), 6.45 (d, 1H, J ) 2.6), 6.38 (dd, 1H, J ) 2.5, J ) 8.0
Hz), 3.73 (s, 3H), 2.59-2.66 (m, 2H), 2.33 (m, 1H), 1.99 (sext,
1H), 1.91 (m, 2H), 1.04 (t, 3H). MS: m/e ) 237 (M + 1). [R]D
20
-108.6 (c ) 1, MeOH). Anal. (C13H16O4) C, H.
Determination of Absolute Stereochemistry. Com-
pound 50. (S,R)-Isomer. Compound 42. The (R,R)-isomer
was treated as described in steps A and C in the procedure as
described above and yielded 50 (S,R)-isomer. Compound 50
was recrystalized from 2-propanol-water to give crystals
suitable from single X-ray crystallographic analysis. The
absolute stereochemistry of 50 was determined to be (R)
relative to the known chiral center of (S)-pantolactone. An
ORTEP structure drawing and coordinates are included in the
Supporting Information.
(2R)-7-[3-(2-Chloro-4-phenoxyphenoxy)propoxy]-2-eth-
ylchromane-2-carboxylic Acid (46). To an 80 mL DMF
solution of (2R)-methyl 2-ethyl-7-hydroxychromane-2-carboxy-
late (44) (2.71 g, 11.5 mmol) and 3-(2-chloro-4-phenoxyphe-
noxy)-1-bromopropane (34) (4.4 g, 13.0 mmol) was added
cesium carbonate (4.1 g, 12.6 mmol). The resulting suspension
was stirred at 65 °C for 5 h. The reaction mixture was diluted
in MTBE and water. The organic layer was separated. The
aqueous layer was extracted twice with MTBE. The combined
organic layers were dried over anhydrous sodium sulfate,
filtered, concentrated, and chromatographed on silica gel.
Elution with 15% AcOEt/hexanes yielded the methyl ester of
the title compound as a pale yellow oil (5.1 g). This material
was dissolved in 175 mL of 2-propanol and 94 mL of 1 N
NaOH(aq). The resulting solution was heated to 70 °C for
overnight. Then, the solvent was removed under reduced
pressure. The residue was dissolved in AcOEt and 2 N HCl-
(aq). The organic layer was separated. The aqueous layer was
extracted twice with AcOEt. The combined organic layers were
dried over anhydrous sodium sulfate, filtered, and concen-
trated to give the title compound as a pale yellow oil (4.48 g).
1
H NMR (500 MHz, CDCl3): δ 7.34 (m, 2H), 7.09 (m, 2H),
6.99-6.89 (m, 5H), 6.54 (d, 1H, J ) 2 Hz), 6.51 (dd, 1H, J )
1.6, 8.2 Hz), 4.20 (t, 2H, J ) 6 Hz), 4.19 (t, 2H, J ) 5.9 Hz),
2.71 (m, 2H), 2.30 (m, 1H), 2.30 (p, 2H, J ) 6 Hz), 2.05-1.90
(m, 3H), 1.06 (t, 3H, J ) 7.4 Hz). MS: m/e ) 483 (M + 1).
Anal. (C27H27O6Cl1) C, H, Cl.
(2S)-7-[3-(2-Chloro-4-phenoxyphenoxy)propoxy]-2-eth-
ylchromane-2-carboxylic Acid (47). 1
H NMR (500 MHz,
CDCl3): δ 7.34 (m, 2H), 7.09 (m, 2H), 6.99-6.89 (m, 5H), 6.54
(d, 1H, J ) 2 Hz), 6.51 (dd, 1H, J ) 1.6, 8.2 Hz), 4.20 (t, 2H,
J ) 6 Hz), 4.19 (t, 2H, J ) 5.9 Hz), 2.71 (m, 2H), 2.3 (m, 1H),
2.30 (p, 2H, J ) 6 Hz), 2.05-1.90 (m, 3H), 1.06 (t, 3H, J ) 7.4
Hz). MS: m/e ) 483 (M + 1). Anal. (C27H27O6Cl1) C, H, Cl.
(2R)-7-{3-(2-Chloro-4-(4-fluorophenoxy)phenoxy]pro-
poxy}-2-ethylchromane-2-carboxylic Acid (48). 1
H NMR
(500 MHz, CDCl3): δ 7.05-7.01 (m, 2H), 6.97-6.9 (m, 5H),
6.86 (dd, 1H J ) 3, J ) 8.9 Hz), 6.55-6.51 (m, 2H), 4.20 (m,
4H), 2.70 (m, 2H), 2.32 (m, 1H), 2.30 (p, 2H, J ) 6 Hz), 2.00
(m, 2H), 1.93 (m, 1H), 1.06 (t, 3H, J ) 7.3 Hz). MS: m/e ) 501
(M + 1). [R]D
20
+59.3 (c ) 1, MeOH) Anal. (C27H26O6F1Cl1) C,
H, F, Cl.
(2S)-7-{3-(2-Chloro-4-(4-fluorophenoxy)phenoxy]pro-
poxy}-2-ethylchromane-2-carboxylic Acid (49). 1
H NMR
(500 MHz, CDCl3): δ 7.05-7.01 (m, 2H), 6.97-6.90 (m, 5H),
6.86 (dd, 1H J ) 3, J ) 8.9 Hz), 6.55-6.51 (m, 2H), 4.20 (m,
4H), 2.70 (m, 2H), 2.32 (m, 1H), 2.30 (p, 2H, J ) 6 Hz), 2.00
(m, 2H), 1.93 (m, 1H), 1.06 (t, 3H, J ) 7.3 Hz). MS: m/e ) 501
(M + 1). Anal. (C27H26O6F1Cl1) C, H, F, Cl.
Acknowledgment. We gratefully acknowledge Mr.
Joseph F. Leone and Drs. Gerard R. Kiecykowski and
Philip Eskola of Synthetic Services Group for large scale
synthetic support. We also thank Dr. Richard G. Ball
and Mrs. Nancy Tsou for the X-ray crystallographic
analysis, and Drs. John G. Menke, Monica Einstein,
William P. Feeney, and Susan A. Iliff for biological
evaluation of compounds.
Supporting Information Available: NMR spectral data
and results of elemental analysis for all final compounds not
included in the Experimental Section and the X-ray crystal-
lographic data of compound 50. This material is available free
of charge via the Internet at http://pubs.acs.org.
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JM030621D
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