The document discusses several physical properties that are important for drug design, including ionization, lipophilicity, hydrogen bonding, and molecular size. It explains how these properties impact key processes in the body like absorption, distribution, metabolism, and excretion of an oral drug. Specifically, it notes that the ionized and un-ionized forms of a drug affect its solubility, binding interactions, and ability to cross membranes in different parts of the body. The optimal lipophilicity and ability to form hydrogen bonds are also important for a drug to effectively reach its target site of action. Understanding these physical chemistry principles can help guide lead optimization and identification in drug discovery programs.
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
This document provides an overview of peptidomimetics. It begins with the evolution of peptidomimetics and how they were developed to overcome limitations of peptides as drugs. It then covers classification of peptidomimetics, design strategies like modifying amino acids and imposing structural constraints, and examples of peptidomimetic drugs that inhibit enzymes like ACE, thrombin, and HIV protease. The document concludes by stating peptidomimetics are an important area of drug design for developing small molecule mimics of peptide functions.
This document provides an overview of prodrug design. It defines a prodrug as an inactive derivative of a drug molecule that undergoes biotransformation to release the active drug. Prodrugs are classified based on their structure and include carrier-linked, bipartite, tripartite, mutual, and bioprecursor prodrugs. The document discusses various rationales for prodrug design such as improving solubility, absorption, patient acceptability, and site-specific drug delivery. Common functional groups used in prodrugs include esters, amides, phosphates, and carbamates. The document also covers practical considerations and approaches for overcoming limitations like pre-systemic metabolism and blood-brain barrier penetration.
1) The document discusses the synthon approach, which involves breaking down a target molecule into simpler starting materials through imaginary bond breaking (disconnection) or functional group interconversion.
2) Key terms are defined, including disconnection, synthon, and functional group interconversion. Basic rules of disconnection are outlined.
3) An example of using the synthon approach to synthesize the drug benzocaine from toluene is provided, outlining the multi-step reaction pathway and identifying specific synthons.
PEPTIDOMIMETICS , HERE WE HAVE INCLUDED THE INTRODUCTION, CLASSIFICATION, ADVANTAGES , DISADVANTAGES, ITS METHODS PREPARATION, PRINCIPLES OD DRUG DESIGN, ITS CHEMISTRY. STEREOCHEMISTRY, SYNTHESIS AND APPLICATIONS
This document discusses peptidomimetics, which are compounds that mimic peptides and proteins while overcoming issues like stability and bioavailability. It defines peptidomimetics and explains their therapeutic values, including antimicrobial, anticancer, antiviral, and analgesic activities. The document also describes two main approaches to designing peptidomimetics: manipulating amino acids, such as substituting them or modifying side chains, and mimicking the peptide backbone through replacements like esters or heterocycles. Specific examples of amino acid and backbone modifications that produce bioactive peptidomimetics are provided.
Global and local restrictions Peptidomimetics ASHOK GAUTAM
Peptidomimetics are small protein-like chains designed to mimic peptides but with greater stability and specificity. They are created either by modifying existing peptides or designing new structures that mimic peptides. Peptidomimetics incorporate conformational constraints locally or globally to restrict flexibility and exclude potential conformations, allowing for more targeted interaction with biological targets. Conformational constraints are needed to improve properties like stability, activity, and selectivity for applications like drug development and targeted cancer therapies. Common constraints include cyclization, disulfide bonds, and restricted amino acids.
This document discusses stereochemistry and its importance in drug action. It defines key terms like chirality, enantiomers, and diastereomers. Many drugs are chiral and exist as two non-superimposable mirror images. The document provides examples of chiral drugs like adrenaline, local anesthetics, inhalational agents, and neuromuscular blocking agents. It discusses how the two enantiomers of a drug can have different pharmacological effects and toxicity profiles. The absorption, distribution, metabolism, and excretion of drug enantiomers may also differ due to stereoselectivity at various biological levels.
Introduction
Classification
Therapeutic values of peptidomimetics
Design of peptidomimetics by manipulation of amino acids
Modification of peptide backbone
Chemistry of prostaglandins, leukotrienes and thromboxanes
This document provides an overview of peptidomimetics. It begins with the evolution of peptidomimetics and how they were developed to overcome limitations of peptides as drugs. It then covers classification of peptidomimetics, design strategies like modifying amino acids and imposing structural constraints, and examples of peptidomimetic drugs that inhibit enzymes like ACE, thrombin, and HIV protease. The document concludes by stating peptidomimetics are an important area of drug design for developing small molecule mimics of peptide functions.
This document provides an overview of prodrug design. It defines a prodrug as an inactive derivative of a drug molecule that undergoes biotransformation to release the active drug. Prodrugs are classified based on their structure and include carrier-linked, bipartite, tripartite, mutual, and bioprecursor prodrugs. The document discusses various rationales for prodrug design such as improving solubility, absorption, patient acceptability, and site-specific drug delivery. Common functional groups used in prodrugs include esters, amides, phosphates, and carbamates. The document also covers practical considerations and approaches for overcoming limitations like pre-systemic metabolism and blood-brain barrier penetration.
1) The document discusses the synthon approach, which involves breaking down a target molecule into simpler starting materials through imaginary bond breaking (disconnection) or functional group interconversion.
2) Key terms are defined, including disconnection, synthon, and functional group interconversion. Basic rules of disconnection are outlined.
3) An example of using the synthon approach to synthesize the drug benzocaine from toluene is provided, outlining the multi-step reaction pathway and identifying specific synthons.
PEPTIDOMIMETICS , HERE WE HAVE INCLUDED THE INTRODUCTION, CLASSIFICATION, ADVANTAGES , DISADVANTAGES, ITS METHODS PREPARATION, PRINCIPLES OD DRUG DESIGN, ITS CHEMISTRY. STEREOCHEMISTRY, SYNTHESIS AND APPLICATIONS
This document discusses peptidomimetics, which are compounds that mimic peptides and proteins while overcoming issues like stability and bioavailability. It defines peptidomimetics and explains their therapeutic values, including antimicrobial, anticancer, antiviral, and analgesic activities. The document also describes two main approaches to designing peptidomimetics: manipulating amino acids, such as substituting them or modifying side chains, and mimicking the peptide backbone through replacements like esters or heterocycles. Specific examples of amino acid and backbone modifications that produce bioactive peptidomimetics are provided.
Global and local restrictions Peptidomimetics ASHOK GAUTAM
Peptidomimetics are small protein-like chains designed to mimic peptides but with greater stability and specificity. They are created either by modifying existing peptides or designing new structures that mimic peptides. Peptidomimetics incorporate conformational constraints locally or globally to restrict flexibility and exclude potential conformations, allowing for more targeted interaction with biological targets. Conformational constraints are needed to improve properties like stability, activity, and selectivity for applications like drug development and targeted cancer therapies. Common constraints include cyclization, disulfide bonds, and restricted amino acids.
This document discusses stereochemistry and its importance in drug action. It defines key terms like chirality, enantiomers, and diastereomers. Many drugs are chiral and exist as two non-superimposable mirror images. The document provides examples of chiral drugs like adrenaline, local anesthetics, inhalational agents, and neuromuscular blocking agents. It discusses how the two enantiomers of a drug can have different pharmacological effects and toxicity profiles. The absorption, distribution, metabolism, and excretion of drug enantiomers may also differ due to stereoselectivity at various biological levels.
Relationship between hansch analysis and free wilson analysisKomalJAIN122
This document provides an overview of quantitative structure-activity relationship (QSAR) modeling techniques including Hansch analysis, Free-Wilson analysis, and Topliss schemes. It discusses how QSAR relates the biological activity of drugs to their physicochemical properties through equations. Specifically, it explains that Hansch equations relate activity to hydrophobicity, electronic effects, and steric factors. Examples of Hansch equations are provided. The Free-Wilson approach derives equations based on the presence or absence of substituents. Topliss schemes provide a methodical approach to substituent selection for optimization.
Drug resistance occurs through several mechanisms: mutation, selective pressure, and gene transfer allow microbes to develop resistance. Strategies to combat resistance include international collaboration on surveillance and incentives for new drugs, national treatment guidelines and education programs, and community efforts like rational antibiotic use and hygiene. Genetic changes allow microbes to develop resistance through various mechanisms like mutation, selective pressure, and horizontal gene transfer between microbes.
Chemistry of prostaglandins, leukotrienes and thromboxanesAbhimanyu Awasthi
The document summarizes a presentation on the chemistry of prostaglandins, leukotrienes, and thromboxanes. Prostaglandins, leukotrienes, and thromboxanes are oxygen metabolites of arachidonic acid that form a family of lipid substances with intrinsic biological activities. They are involved in processes like inflammation, platelet aggregation, and vascular homeostasis. The presentation covers their biosynthesis from arachidonic acid, sub-families, properties, and biologically important examples like prostacyclin, thromboxane A2, and leukotriene B4. It also discusses the enzymes and pathways involved in their synthesis.
This powerpoint presentation will help to know about introduction of bioisosterism by Biotechnology point of view. Hope this powerpoint presentation will your reference.
This document discusses structure-activity relationships (SAR) and how medicinal chemistry uses SAR to develop new drugs. It defines SAR as the relationship between a molecule's structure and its biological activity. Medicinal chemists analyze how structural modifications affect biological properties in order to determine which parts of a molecule are responsible for its effects. The goal is to optimize desired effects and minimize unwanted side effects by making targeted changes to a lead compound's structure. The document provides several examples of drugs that were developed through systematic SAR studies of existing compounds.
This document summarizes several organic reactions used in heterocyclic chemistry. It describes the Debus–Radziszewski reaction for imidazole synthesis, the Knorr reaction for pyrrole synthesis, the Pinner reaction for pyrimidine synthesis, the Combes reaction for quinoline synthesis, the Bernthsen reaction for acridine synthesis, the Smiles rearrangement, and the Traube reaction for purine synthesis. For each reaction, it provides the starting materials, product, mechanism, and some applications. The document is intended to present an overview of important heterocyclic reactions for students of pharmaceutical chemistry.
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
QSAR attempts to correlate biological activity to measurable physicochemical properties through mathematical equations. It relates parameters like lipophilicity (log P), electronic effects (Hammett constants), and steric effects to biological response. Various QSAR methods exist, including Hansch analysis which uses these substituent constants in its equations. More advanced techniques like CoMFA analyze fields around aligned molecules to model activity landscapes and identify favorable regions for activity. QSAR provides a framework for drug design and predicting activities of untested compounds.
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
The document discusses pharmacophores, which are abstract descriptions of molecular features necessary for molecular recognition between a ligand and biological macromolecule. A pharmacophore consists of 3D structural features like hydrophobic groups and hydrogen bond donors/acceptors. Pharmacophore mapping is used to define pharmacophoric features and align molecules to identify common binding elements responsible for biological activity. Pharmacophore models can be used in virtual screening to filter large databases and identify new compounds that may bind similarly to known active molecules. The document provides details on different approaches for pharmacophore generation and searching compound libraries.
The document provides an overview of the modern drug discovery process, focusing on lead identification and lead optimization. It discusses how lead compounds are initially identified through screening compound libraries or structure-based drug design. These leads are then optimized through chemical modifications to improve properties like efficacy, potency, pharmacokinetics and toxicity profile. The goal is to develop compounds suitable for preclinical and clinical testing towards becoming an approved drug. Methods for lead optimization include modifying functional groups, exploring structure-activity relationships, and altering aspects like stereochemistry.
This document discusses biological drug targets and summarizes key points about receptors and drug-receptor interactions. It begins with an introduction to biological drug targets and explains that drugs produce their effects by binding to receptors and causing biochemical or physical changes. It then discusses the main types of receptors - ligand-gated ion channels, G-protein coupled receptors, kinase-linked receptors, and nuclear receptors. Theories of drug-receptor interaction are also summarized, including occupancy theory, rate theory, induced fit theory, and others. Finally, the document briefly introduces artificial enzymes as synthetic molecules that can mimic the functions of natural enzymes.
Heterocyclic Organic Reaction - By Vishal DakhaleVishalDakhale
This document discusses three heterocyclic organic reactions: the Debus-Radziszewski imidazole synthesis, the Knorr pyrazole synthesis, and the Combes quinoline synthesis. The Debus-Radziszewski reaction synthesizes imidazoles from a dicarbonyl, aldehyde, and ammonia. The Knorr reaction synthesizes pyrazoles from hydrazines and 1,3-dicarbonyl compounds using an acid catalyst. The Combes reaction synthesizes quinolines by condensing unsubstituted anilines with β-diketones followed by an acid-catalyzed ring closure.
This presentation gives us an information regarding the protease enzyme and its development ,development of agents using molecular modelling techniques
Role of chirality in stereoselective and specific theraputic agentKaranvir Rajput
This document discusses the role of chirality in selective therapeutic agents. It begins by defining isomerism and the different types of isomers including constitutional, stereoisomers, optical isomers, enantiomers, and diastereomers. It then discusses the discovery of optical activity and chirality. The key points are that humans are chiral beings and the enantiomers of chiral drugs may have different biological effects. Several examples are given to illustrate how the biological activity of enantiomers can differ, including some being more active, having opposing effects, or one causing toxicity. The importance of understanding chirality in drug development and safety is emphasized.
Synthetic Reagent and Its Applications (M. Pharm)MohdShafeeque4
The document summarizes various synthetic reagents and their applications. It describes 12 reagents including aluminium isopropoxide, N-bromosuccinimide, diazomethane, dicyclohexylcarbodiimide, Wilkinson reagent, Wittig reagent, osmium tetroxide, titanium chloride, diazopropane, diethyl azodicarboxylate, triphenylphosphine, and BOP reagent. For each reagent, it provides information on chemical formula, structure, preparation method, and typical applications. The document serves as a useful reference for organic chemistry students and researchers.
Prostaglandins and leukotrienes are eicosanoids derived from arachidonic acid. They were first discovered in seminal fluid in the 1930s. Prostaglandins are synthesized via the cyclooxygenase pathway while leukotrienes are synthesized via the lipoxygenase pathway. These lipid mediators act on specific G-protein coupled receptors and are involved in various physiological processes like contraction and relaxation of smooth muscles, inflammation, and platelet aggregation. Due to their role in inflammation and bronchoconstriction, leukotriene receptor antagonists are used to treat asthma.
The document summarizes Wittig reagent, which is also known as triphenyl phosphoniumylide or alkylidenephosphorane. It forms when triphenyl phosphine reacts with an alkyl halide via an SN2 reaction followed by deprotonation. Wittig reagent is used to incorporate exocyclic methylene groups and synthesize indoles, alpha,beta-unsaturated esters, dienes, olefins, aldehydes, and natural compounds like squalene and beta-carotene. It has various applications in organic synthesis due to its ability to generate carbon-carbon double bonds.
CHEMISTRY OF PEPTIDES [M.PHARM, M.SC, BSC, B.PHARM]Shikha Popali
THE CHEMISTRY OF PEPTIDES THE DIFFICULT TO COLLECT DATA FOR READERS , THREFORE HERE WE HAVE COLLECTED ALL THE DATA AT A PLACE AND PROVIDED EASIER TO CHEMISTRIANS.
The Importance of Product Design
It may seem obvious to state that a new product should be adequately defined before any serious product development is undertaken.
In many cases, the value of the design phase is often underestimated in the rush to start development and get products to the market quickly.
This can result in much wasted time and valuable resources. It can also lead to reduced staff motivation if a product is developed that is not wanted or if the product definition is constantly changing during development.
The quality of the design activities can strongly influence the success of the development of the right product to the market and ultimate return on investment (ROI).
The document discusses various physicochemical properties of drugs that influence their biological activity and effects. It covers properties like solubility, partition coefficient, dissociation constant, hydrogen bonding, ionization, complexation, and stereochemistry. Solubility and partition coefficient affect absorption and distribution of drugs in the body. Ionization influences what form a drug is in and its ability to cross membranes. Hydrogen bonding and complexation can impact properties like boiling point and drug availability. Protein binding and stereochemistry also influence a drug's pharmacological effects. Understanding these physicochemical properties is important for drug design and development.
Relationship between hansch analysis and free wilson analysisKomalJAIN122
This document provides an overview of quantitative structure-activity relationship (QSAR) modeling techniques including Hansch analysis, Free-Wilson analysis, and Topliss schemes. It discusses how QSAR relates the biological activity of drugs to their physicochemical properties through equations. Specifically, it explains that Hansch equations relate activity to hydrophobicity, electronic effects, and steric factors. Examples of Hansch equations are provided. The Free-Wilson approach derives equations based on the presence or absence of substituents. Topliss schemes provide a methodical approach to substituent selection for optimization.
Drug resistance occurs through several mechanisms: mutation, selective pressure, and gene transfer allow microbes to develop resistance. Strategies to combat resistance include international collaboration on surveillance and incentives for new drugs, national treatment guidelines and education programs, and community efforts like rational antibiotic use and hygiene. Genetic changes allow microbes to develop resistance through various mechanisms like mutation, selective pressure, and horizontal gene transfer between microbes.
Chemistry of prostaglandins, leukotrienes and thromboxanesAbhimanyu Awasthi
The document summarizes a presentation on the chemistry of prostaglandins, leukotrienes, and thromboxanes. Prostaglandins, leukotrienes, and thromboxanes are oxygen metabolites of arachidonic acid that form a family of lipid substances with intrinsic biological activities. They are involved in processes like inflammation, platelet aggregation, and vascular homeostasis. The presentation covers their biosynthesis from arachidonic acid, sub-families, properties, and biologically important examples like prostacyclin, thromboxane A2, and leukotriene B4. It also discusses the enzymes and pathways involved in their synthesis.
This powerpoint presentation will help to know about introduction of bioisosterism by Biotechnology point of view. Hope this powerpoint presentation will your reference.
This document discusses structure-activity relationships (SAR) and how medicinal chemistry uses SAR to develop new drugs. It defines SAR as the relationship between a molecule's structure and its biological activity. Medicinal chemists analyze how structural modifications affect biological properties in order to determine which parts of a molecule are responsible for its effects. The goal is to optimize desired effects and minimize unwanted side effects by making targeted changes to a lead compound's structure. The document provides several examples of drugs that were developed through systematic SAR studies of existing compounds.
This document summarizes several organic reactions used in heterocyclic chemistry. It describes the Debus–Radziszewski reaction for imidazole synthesis, the Knorr reaction for pyrrole synthesis, the Pinner reaction for pyrimidine synthesis, the Combes reaction for quinoline synthesis, the Bernthsen reaction for acridine synthesis, the Smiles rearrangement, and the Traube reaction for purine synthesis. For each reaction, it provides the starting materials, product, mechanism, and some applications. The document is intended to present an overview of important heterocyclic reactions for students of pharmaceutical chemistry.
Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound
QSAR attempts to correlate biological activity to measurable physicochemical properties through mathematical equations. It relates parameters like lipophilicity (log P), electronic effects (Hammett constants), and steric effects to biological response. Various QSAR methods exist, including Hansch analysis which uses these substituent constants in its equations. More advanced techniques like CoMFA analyze fields around aligned molecules to model activity landscapes and identify favorable regions for activity. QSAR provides a framework for drug design and predicting activities of untested compounds.
stereochemistry and drug action ; basic introduction about stereochemistry and stereoisomers ; pharmacokinetic and pharmacodynamics concept of stereochemistry ; easson Stedman hypothesis ; stereo selectivity criteria .
The document discusses pharmacophores, which are abstract descriptions of molecular features necessary for molecular recognition between a ligand and biological macromolecule. A pharmacophore consists of 3D structural features like hydrophobic groups and hydrogen bond donors/acceptors. Pharmacophore mapping is used to define pharmacophoric features and align molecules to identify common binding elements responsible for biological activity. Pharmacophore models can be used in virtual screening to filter large databases and identify new compounds that may bind similarly to known active molecules. The document provides details on different approaches for pharmacophore generation and searching compound libraries.
The document provides an overview of the modern drug discovery process, focusing on lead identification and lead optimization. It discusses how lead compounds are initially identified through screening compound libraries or structure-based drug design. These leads are then optimized through chemical modifications to improve properties like efficacy, potency, pharmacokinetics and toxicity profile. The goal is to develop compounds suitable for preclinical and clinical testing towards becoming an approved drug. Methods for lead optimization include modifying functional groups, exploring structure-activity relationships, and altering aspects like stereochemistry.
This document discusses biological drug targets and summarizes key points about receptors and drug-receptor interactions. It begins with an introduction to biological drug targets and explains that drugs produce their effects by binding to receptors and causing biochemical or physical changes. It then discusses the main types of receptors - ligand-gated ion channels, G-protein coupled receptors, kinase-linked receptors, and nuclear receptors. Theories of drug-receptor interaction are also summarized, including occupancy theory, rate theory, induced fit theory, and others. Finally, the document briefly introduces artificial enzymes as synthetic molecules that can mimic the functions of natural enzymes.
Heterocyclic Organic Reaction - By Vishal DakhaleVishalDakhale
This document discusses three heterocyclic organic reactions: the Debus-Radziszewski imidazole synthesis, the Knorr pyrazole synthesis, and the Combes quinoline synthesis. The Debus-Radziszewski reaction synthesizes imidazoles from a dicarbonyl, aldehyde, and ammonia. The Knorr reaction synthesizes pyrazoles from hydrazines and 1,3-dicarbonyl compounds using an acid catalyst. The Combes reaction synthesizes quinolines by condensing unsubstituted anilines with β-diketones followed by an acid-catalyzed ring closure.
This presentation gives us an information regarding the protease enzyme and its development ,development of agents using molecular modelling techniques
Role of chirality in stereoselective and specific theraputic agentKaranvir Rajput
This document discusses the role of chirality in selective therapeutic agents. It begins by defining isomerism and the different types of isomers including constitutional, stereoisomers, optical isomers, enantiomers, and diastereomers. It then discusses the discovery of optical activity and chirality. The key points are that humans are chiral beings and the enantiomers of chiral drugs may have different biological effects. Several examples are given to illustrate how the biological activity of enantiomers can differ, including some being more active, having opposing effects, or one causing toxicity. The importance of understanding chirality in drug development and safety is emphasized.
Synthetic Reagent and Its Applications (M. Pharm)MohdShafeeque4
The document summarizes various synthetic reagents and their applications. It describes 12 reagents including aluminium isopropoxide, N-bromosuccinimide, diazomethane, dicyclohexylcarbodiimide, Wilkinson reagent, Wittig reagent, osmium tetroxide, titanium chloride, diazopropane, diethyl azodicarboxylate, triphenylphosphine, and BOP reagent. For each reagent, it provides information on chemical formula, structure, preparation method, and typical applications. The document serves as a useful reference for organic chemistry students and researchers.
Prostaglandins and leukotrienes are eicosanoids derived from arachidonic acid. They were first discovered in seminal fluid in the 1930s. Prostaglandins are synthesized via the cyclooxygenase pathway while leukotrienes are synthesized via the lipoxygenase pathway. These lipid mediators act on specific G-protein coupled receptors and are involved in various physiological processes like contraction and relaxation of smooth muscles, inflammation, and platelet aggregation. Due to their role in inflammation and bronchoconstriction, leukotriene receptor antagonists are used to treat asthma.
The document summarizes Wittig reagent, which is also known as triphenyl phosphoniumylide or alkylidenephosphorane. It forms when triphenyl phosphine reacts with an alkyl halide via an SN2 reaction followed by deprotonation. Wittig reagent is used to incorporate exocyclic methylene groups and synthesize indoles, alpha,beta-unsaturated esters, dienes, olefins, aldehydes, and natural compounds like squalene and beta-carotene. It has various applications in organic synthesis due to its ability to generate carbon-carbon double bonds.
CHEMISTRY OF PEPTIDES [M.PHARM, M.SC, BSC, B.PHARM]Shikha Popali
THE CHEMISTRY OF PEPTIDES THE DIFFICULT TO COLLECT DATA FOR READERS , THREFORE HERE WE HAVE COLLECTED ALL THE DATA AT A PLACE AND PROVIDED EASIER TO CHEMISTRIANS.
The Importance of Product Design
It may seem obvious to state that a new product should be adequately defined before any serious product development is undertaken.
In many cases, the value of the design phase is often underestimated in the rush to start development and get products to the market quickly.
This can result in much wasted time and valuable resources. It can also lead to reduced staff motivation if a product is developed that is not wanted or if the product definition is constantly changing during development.
The quality of the design activities can strongly influence the success of the development of the right product to the market and ultimate return on investment (ROI).
The document discusses various physicochemical properties of drugs that influence their biological activity and effects. It covers properties like solubility, partition coefficient, dissociation constant, hydrogen bonding, ionization, complexation, and stereochemistry. Solubility and partition coefficient affect absorption and distribution of drugs in the body. Ionization influences what form a drug is in and its ability to cross membranes. Hydrogen bonding and complexation can impact properties like boiling point and drug availability. Protein binding and stereochemistry also influence a drug's pharmacological effects. Understanding these physicochemical properties is important for drug design and development.
The document discusses drug metabolism and the role of metabolic pathways in facilitating drug elimination from the body. It notes:
- Metabolism converts lipophilic drugs into more polar, water-soluble metabolites that can be readily excreted, enhancing drug elimination and producing inactive compounds.
- Drug metabolism involves two main phases: phase I reactions introduce functional groups through oxidation, reduction or hydrolysis, while phase II reactions conjugate these groups with endogenous compounds like glucuronic acid to form water-soluble conjugates that are excreted.
- The liver is the most important organ for drug metabolism due to its abundance of metabolizing enzymes, though the intestine also plays a role through hydrolysis and bacterial reduction
1) The document discusses acid-base balance and homeostasis, explaining key concepts such as pH, buffers, and the importance of tightly regulating hydrogen ion concentration.
2) It describes the major systems that regulate acid-base balance - respiratory (lungs), renal (kidneys), and buffers. The lungs and kidneys help eliminate or retain bicarbonate and titrate hydrogen ions to maintain normal pH.
3) Even slight deviations from the normal pH range can impact cell function, enzyme activity, and other physiological processes since hydrogen ions are highly reactive. Tight control is needed to support life.
Physicochemical parameters in relation to Biological activitiesSKarthigaSVCP
This document discusses various physicochemical parameters that influence drug solubility, ionization, and biological activity. It defines key concepts like solubility, partition coefficient, ionization, protein binding, hydrogen bonding, and stereochemistry. Solubility depends on interactions between solute and solvent properties. Partition coefficient indicates how drugs distribute between aqueous and lipid phases. Ionization influences whether drugs are charged or uncharged. Protein binding, hydrogen bonding, and complexation impact how drugs interact with biological targets and receptors. Stereochemistry, including conformational, optical, and geometrical isomers, also influences pharmacological properties and effects. Understanding these physicochemical parameters is important for drug design and development.
The document discusses apolipoproteins, which are protein components of lipoproteins that transport lipids in the blood. It describes the structure and function of various apolipoproteins, including apo A1, apo E, and apo B. Apo B plays an important role in lipoprotein formation and cholesterol transport, and mutations in the apo B gene can cause disorders with abnormal lipid levels like hypobetalipoproteinemia or hypercholesterolemia.
Lipinski's Rule of Five is a rule of thumb used to evaluate how easily a pharmaceutical drug can be absorbed by the body. It states that, in general, an orally active drug has no more than one violation of the following criteria: a molecular weight under 500 Daltons, no more than 5 hydrogen bond donors, no more than 10 hydrogen bond acceptors, and an octanol-water partition coefficient (clog P) of less than 5. The rule aims to assess whether a compound poses suitable pharmacokinetic properties to be an orally active drug in humans. Over time, extensions to the rule have been proposed to better evaluate druglikeness.
The document discusses several key physicochemical properties that influence a drug's biological activity, including:
1. Partition coefficient, which measures a drug's relative solubility in water vs. lipid and predicts its distribution in the body.
2. Acidity and basicity, with ionization affecting absorption, transport, binding, and elimination. The Henderson-Hasselbalch equation calculates the percentage of a drug in its ionized and unionized forms.
3. Steric factors like a drug's bulk, size, and shape, which can either hinder or help its interaction with receptors and enzymes. A drug's physicochemical properties are crucial to its ability to reach biological targets.
Phsicochemical properties according to pci syllubus.
The ability of a chemical compound to elicit a pharmacological/ therapeutic effect is related to the influence of various physical and chemical (physicochemical) properties of the chemical substance on the bio molecule that it interacts with.
1)Physical Properties : Physical property of drug is responsible for its action
2)Chemical Properties :The drug react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc.
The ability of a chemical compound to elicit a pharmacological/ therapeutic effect is related to the influence of various physical and chemical (physicochemical) properties of the chemical substance on the bio molecule that it interacts with.
1)Physical Properties : Physical property of drug is responsible for its action
2)Chemical Properties :The drug react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc.
Properties of GI tract, pH partition hypothesis Naveen Reddy
Drug absorption from the gastrointestinal (GI) tract depends on several physiological factors:
1) Gastric emptying and intestinal transit time influence drug absorption by determining how long drugs remain in areas where absorption can occur. Faster emptying and transit generally increase absorption rate.
2) Water fluxes in the GI tract can impact drug dissolution and movement within the lumen, affecting absorption. Considerable water is secreted in the small intestine and mostly reabsorbed.
3) The permeability of drugs is affected by their solubility, ionization state, and lipophilicity, which determine how well drugs can pass through membranes according to the pH partition hypothesis. However, the microclimate pH at the membrane surface can differ
The document discusses acid-base disorders and summarizes:
1) Acid-base disorders occur when the body's normal balance of acids and bases deviates from the normal pH range, causing acidosis or alkalosis. Disorders can be classified as respiratory or metabolic based on their etiology.
2) Biochemical findings include concepts of acids and bases donating and accepting protons. The strongest acid and base present in water are H3O+ and OH-.
3) Regulation of acid-base balance involves chemical buffer systems, respiratory mechanisms, and renal mechanisms working together to precisely control pH levels.
The document discusses acid-base balance and its regulation in the human body, including the three-tier mechanism of chemical buffers, respiratory regulation, and renal regulation that maintain pH levels. It also covers approaches to diagnosing acid-base disorders, concepts like anion gap and delta ratio, and provides examples of case studies of different acid-base disorders.
Drug metabolism involves converting lipophilic compounds into hydrophilic derivatives that can be readily excreted. This occurs mainly through oxidation, reduction and hydrolysis reactions in the liver and intestines (Phase I), followed by conjugation reactions that attach groups like glucuronic acid to facilitate excretion (Phase II). Many factors can influence an individual's drug metabolism, like age, species, genetics, sex, and interactions between drugs and foods that induce or inhibit metabolic enzymes. Understanding these metabolic pathways and factors is important for predicting drug interactions and toxicity.
The document discusses the pH partition hypothesis, which states that the absorption of drugs across biomembranes is governed by the drug's dissociation constant (pKa), lipid solubility of the un-ionized form, and the pH of the absorption site. According to the hypothesis, only the un-ionized form of an acid or base drug can be absorbed if it is sufficiently lipid soluble. The fraction of a drug in its un-ionized form can be calculated using the Henderson-Hasselbach equation based on the drug's pKa and the pH. However, the pH partition theory is an oversimplification and does not always accurately predict drug absorption behavior.
This document provides an overview of buffers in biological systems. It discusses how biological buffers help maintain pH within a narrow physiological range through reversible acid-base reactions. The key types of biological buffers mentioned are bicarbonate, phosphate, proteins, and hemoglobin. Bicarbonate buffers blood pH through reactions involving carbonic acid and carbon dioxide transport. Phosphate buffers intracellular and renal fluid. Proteins and hemoglobin buffer through amino acid side chains that react with hydrogen ions. Maintaining pH is critical for biochemical processes and homeostasis in living organisms.
Buffers biological systems acid base imbalance pH protein bicarbonate hemoglobin amino acid phosphate kidney lungs bone .............................................................................................................................................................................................................................................................................
Lycopene is a red carotenoid pigment found in tomatoes and other red fruits and vegetables. It has antioxidant properties and can help reduce the risk of certain cancers. Lycopene is absorbed into the body after being dissolved in lipids in the digestive system. Processing foods like cooking tomatoes can increase lycopene's bioavailability. As an antioxidant, lycopene acts by quenching singlet oxygen and peroxyl radicals through adduct formation, electron transfer, or hydrogen abstraction reactions.
Importance of partition coefficient, solubility and dissociation on pre-formu...SHANE_LOBO145
This document discusses the importance of preformulation studies, specifically focusing on partition coefficient, dissociation constant, and solubility. It defines these key terms and explains their significance in determining drug absorption and developing drug formulations. The partition coefficient indicates a drug's lipophilicity and ability to cross cell membranes. The dissociation constant and Henderson-Hasselbalch equation are used to predict drug ionization and site of absorption in the gastrointestinal tract. Solubility is critical for bioavailability and influences formulation strategies to increase or decrease a drug's aqueous solubility. Understanding these physicochemical properties is essential for designing an optimal drug delivery system.
Rhubarb is a general term used for the cultivated plants in the genus Rheum in the family Polygonaceae. It is a herbaceous perennial growing from short, thick rhizomes. Historically, different plants have been called "rhubarb" in English.
This document summarizes the botanical and chemical properties of liquorice. It describes liquorice as coming from the Glycyrrhiza glabra plant, native to India and China. Microscopically, it contains structures like cork, fibers, and starch. Chemically, it is known to contain saponins like glycyrrhetinic acid. It has various traditional medical uses as an expectorant and treatment for peptic ulcers. It is also used as a flavoring agent in foods and beverages.
Dioscorea is a genus of over 600 species of flowering plants in the family Dioscoreaceae, native throughout the tropical and warm temperate regions of the world. The vast majority of the species are tropical, with only a few species extending into temperate climates.
Digitalis purpurea is a species of flowering plant in the plantain family Plantaginaceae, native to and widespread throughout most of temperate Europe. It is also naturalised in parts of North America and some other temperate regions.
Visnaga consists of the dried ripe fruits of Ammi visnaga Linn, a plant native to Europe, Asia, and North Africa that is cultivated in Egypt and Chile. It has aromatic brown fruits that are 2.25mm in length, 0.7-1.3mm in width, and 0.8-1.1mm in thickness. Visnaga contains furocoumarin and pyranocoumarin derivatives like visnagin and khellin that give it smooth muscle relaxing properties used to treat conditions like asthma, whooping cough, kidney stones, and myocardial damage.
Ginseng is a perennial plant with fleshy roots belonging to the genus Panax. The two most common varieties are Asian ginseng (Panax ginseng) and American ginseng (Panax quinquefolius). Ginseng grows wild in northeast Asia and North America. It has been used in traditional Chinese medicine to treat various conditions like erectile dysfunction, cardiovascular issues, cancer, and weight control. The active compounds in ginseng include ginsenosides, polysaccharides, and fatty acids. Common side effects of ginseng include insomnia, diarrhea, and skin rashes if taken in excessive amounts.
Beeswax is a wax produced by honey bees of the genus Apis. It is processed from the honeycomb after the honey is removed. The wax comb is broken up and boiled to extract the wax. It is then purified by heating and settling. Beeswax is yellow to brown in color with a honey-like odor. It is insoluble in water but soluble in organic solvents and oils. Its main uses are in making candles, polishes, ointments, and cosmetics.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by...Donc Test
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Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
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Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
2. Introduction
Ionisation
Lipophilicity
Hydrogen bonding
Molecular size
Rotatable bonds
Bulk physical properties
Lipinski Rule of Five
The Drug Design Conundrum
Overview
Two lectures
3. An oral drug must be able to:
dissolve
survive a range of pHs (1.5 to
8.0)
survive intestinal bacteria
cross membranes
survive liver metabolism
avoid active transport to bile
avoid excretion by kidneys
partition into target organ
avoid partition into undesired
places (e.g. brain, foetus)
What must a drug do other than bind?
liver
bile
duct
kidneys
bladder
BBB
4. So, before the drug reaches its active site, there are many hurdles
to overcome.
However, many complicated biological processes can be modelled
using simple physical chemistry models or properties – and
understanding these often drives both the lead optimisation and
lead identification phases of a drug discovery program forward.
This lecture will focus on oral therapy, but remember that there are
lots of other methods of administration e.g. intravenous, inhalation,
topical. These will have some of the same, and some different,
hurdles.
Why are physical properties
important in medicinal chemistry?
5. Reducing the complexity
Biological process in
drug action
Dissolution of drug in
gastrointestinal fluids
Absorption from small
intestine
Blood protein
binding
Distribution of
compound in tissues
Physical chemistry
model
Solubility in buffer,
acid or base
logP, logD, polar
surface area, hydrogen
bond counts, MWt
Plasma protein binding,
logP and logD
logP, acid or base
Underlying physical
chemistry
Energy of dissolution;
lipophilicity & crystal
packing
Diffusion rate, membrane
partition coefficient
Binding affinity to blood
proteins e.g. albumin
Binding affinity to cellular
membranes
6. Ionisation
Ionisation = protonation or deprotonation resulting in charged
molecules
About 85% of marketed drugs contain functional groups that are
ionised to some extent at physiological pH (pH 1.5 – 8).
The acidity or basicity of a compound plays a major role in controlling:
Absorption and transport to site of action
• Solubility, bioavailability, absorption and cell penetration, plasma
binding, volume of distribution
Binding of a compound at its site of action
• un-ionised form involved in hydrogen bonding
• ionised form influences strength of salt bridges or H-bonds
Elimination of compound
• Biliary and renal excretion
• CYP P450 metabolism
7. So the same compound will
be ionised to different extents
in different parts of the body.
This means that, for example,
basic compounds will not be
so well absorbed in the
stomach than acidic
compounds since it is
generally the unionised form
of the drug which diffuses into
the blood stream.
How does pH vary in the body?
Fluid pH
Aqueous humour 7.2
Blood 7.4
Colon 5-8
Duodenum (fasting) 4.4-6.6
Duodenum (fed) 5.2-6.2
Saliva 6.4
Small intestine 6.5
Stomach (fasting) 1.4-2.1
Stomach (fed) 3-7
Sweat 5.4
Urine 5.5-7.0
8. When an acid or base is 50% ionised:
pH = pKa
For an
acid:
Ka =
[H+
][A-
]
[AH]
% ionised =
100
1 + 10(pKa - pH)
HA H
+
+ A
Ka
H
+
+ BBH+ Ka
Ka =
[H+
][B]
[BH+] % ionised =
100
1 + 10(pH - pKa)
For a
base:
The equilibrium between un-ionised and ionised forms
is defined by the acidity constant Ka or pKa = -log10 Ka
Ionisation constants
10. 0
10
20
30
40
50
60
70
80
90
100
3 4 5 6 7 8 9 10 11
pH
percent
% neutral
% cation
N
+
NH2
H
N
NH2
-H+
pKa = 9.1
Ionisation of an base – 4-aminopyridine
11. Effect of ionisation on antibacterial potency
of sulphonamides
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
2 3 4 5 6 7 8 9 10 11
pKa
potency
R1
S
N
R2
O O
H
R1
S
N
R2
O O
-
From pH 11 to 7
potency increases
since active species
is the anion.
From pH 7 to 3
potency decreases
since only the neutral
form of the
compound can
transport into the cell.
12. -1
0
1
2
3
4
5
-0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8
3-NO23-CN
3-Cl
3-F
4-Cl
H
4-F
3-Me
4-Me
log(KX/KH) benzoic acids
log(KX/KH)pyridines
N
X
O OH
X
Substituents have similar effects on the ionisation of different series of
compounds.
Trends such as this
are found for a very
wide range of
aromatic ionising
functionalities. This
allows prediction of
the pKa of molecules
before they are even
made!
This is an
example of a
linear free energy
relationship.
Effects of substituents on ionisation
13. Lipophilicity (‘fat-liking’) is the most important physical property of a drug
in relation to its absorption, distribution, potency, and elimination.
Lipophilicity is often an important factor in all of the following, which
include both biological and physicochemical properties:
Solubility
Absorption
Plasma protein binding
Metabolic clearance
Volume of distribution
Enzyme / receptor binding
Biliary and renal clearance
CNS penetration
Storage in tissues
Bioavailability
Toxicity
Lipophilicity
14. The hydrophobic effect
This is entropy driven (remember δG = δH – TδS). Hydrophobic
molecules are encouraged to associate with each other in water.
Placing a non-polar surface into water disturbs network of water-water
hydrogen bonds. This causes a reorientation of the network of hydrogen
bonds to give fewer, but stronger, water-water H-bonds close to the non-
polar surface.
Water molecules close to a non-polar surface consequently exhibit
much greater orientational ordering and hence lower entropy than bulk
water.
Molecular interactions – why don’t oil and water mix?
H
H
H
H
H
H
HH
H
H
H
H
O
H
H
O
H
H
H
O
H
H
O
H
H
O H
H O
H
H
H
O
H
O
H
H
O
H
H
H
O O
H
H
H
O
H
H
O
H
O
H H
15. The hydrophobic effect
This principle also applies to the physical properties of drug molecules.
If a compound is too lipophilic, it may
be insoluble in aqueous media (e.g. gastrointestinal fluid or blood)
bind too strongly to plasma proteins and therefore the free blood
concentration will be too low to produce the desired effect
distribute into lipid bilayers and be unable to reach the inside of the cell
Conversely, if the compound is too polar, it may not be absorbed through
the gut wall due to lack of membrane solubility.
So it is important that the lipophilicity of a potential drug molecule is correct.
How can we measure this?
16. 1-Octanol is the most frequently used lipid phase in pharmaceutical
research. This is because:
It has a polar and non polar region (like a membrane phospholipid)
Po/w is fairly easy to measure
Po/w often correlates well with many biological properties
It can be predicted fairly accurately using computational models
Xaqueous Xoctanol
P
Partition coefficient P (usually expressed as log10P or logP) is defined as:
P =
[X]octanol
[X]aqueous
P is a measure of the relative affinity of a molecule for the lipid and aqueous
phases in the absence of ionisation.
Partition coefficients
17. LogP for a molecule can be calculated from a sum of fragmental
or atom-based terms plus various corrections.
logP = S fragments + S corrections
C: 3.16 M: 3.16 PHENYLBUTAZONE
Class | Type | Log(P) Contribution Description Value
FRAGMENT | # 1 | 3,5-pyrazolidinedione -3.240
ISOLATING |CARBON| 5 Aliphatic isolating carbon(s) 0.975
ISOLATING |CARBON| 12 Aromatic isolating carbon(s) 1.560
EXFRAGMENT|BRANCH| 1 chain and 0 cluster branch(es) -0.130
EXFRAGMENT|HYDROG| 20 H(s) on isolating carbons 4.540
EXFRAGMENT|BONDS | 3 chain and 2 alicyclic (net) -0.540
RESULT | 2.11 |All fragments measured clogP 3.165
clogP for windows output
N
N
C
C
C
C
C
C
C
O
C
C
O
C
C
C
C
C
C
C
C
C
C
H
H
H
H
H H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Phenylbutazone
Branch
Calculation of logP
18. 6.5
7
7.5
8
8.5
9
2 3 4 5 6
logP
pIC50 Blood clot preventing activity
of salicylic acids
O OH
OH
R2R1
O OH
O
O
Aspirin
19. logP
Binding to
enzyme /
receptor
Aqueous
solubility
Binding to
P450
metabolising
enzymes
Absorption
through
membrane
Binding to
blood / tissue
proteins –
less drug free
to act
Binding to
hERG heart
ion channel -
cardiotoxicity
risk
So log P needs to be optimised
What else does logP affect?
20. If a compound can ionise then the observed partitioning between water and
octanol will be pH dependent.
[un-ionised]aq
[ionised]aq
[un-ionised]octanol insignificant
Ka
P
octanol phase
aqueous phase
Distribution
coefficient D (usually
expressed as logD)
is the effective
lipophilicity of a
compound at a given
pH, and is a function
of both the
lipophilicity of the
un-ionised
compound and the
degree of ionisation.
For an acidic compound: HAaq H+
aq A-
aq+
D =
[HA]octanol
[HA]aq [A-
]aq+
For a basic compound: BH+
aq H+
aq Baq+
D =
[B]octanol
[BH+]aq [B]aq+
Distribution coefficients
22. Amlodipine
pKa=9.3
For singly ionising bases in general:
logD = logP - log[1 + 10(pKa-pH)
]
pH - Distribution behaviour of bases
-3
-2
-1
0
1
2
3
4
-4
3 4 5 6 7 8 9 10 11
pH
logD
N
H
O
O
O
O
Cl
O
NH2
N
H
O
O
O
O
Cl
O
NH3+
N
N
H
S
N
H
N
N
H
CN
Cimetidine
pKa=6.8
NH+
N
H
S
N
H
N
N
H
CN
24. e.g. Monocarboxylate transporter 1 blockers
How can lipophilicity be altered?
N
N S
N
O
R2
R1
X
Ar
O
O
N
OH
N
N
OH
N
F
N
N
OH
OH
N
OH
O
N
O
OH
N
N
O
OH
CF3
N
R2
R1
X
Ar
logD 1.7 2.0 1.2 2.9 2.2 3.2
25. e.g. Monocarboxylate transporter 1 blockers
How can lipophilicity be altered?
N
N S
N
O
R2
R1
X
Ar
O
O
N
OH
N
N
OH
N
F
N
N
OH
OH
N
OH
O
N
O
OH
N
N
O
OH
CF3
N
R2
R1
X
Ar
logD 1.7 2.0 1.2 2.9 2.2 3.2
26. Hydrogen bonding
Intermolecular hydrogen bonds are virtually non-existent between small
molecules in water. To form a hydrogen bond between a donor and
acceptor group, both the donor and the acceptor must first break their
hydrogen bonds to surrounding water molecules
A H OH2 B HOH A H B HOH OH2+ +
The position of this equilibrium depends on the relative energies of the
species on either side, and not just the energy of the donor-acceptor
complex
Intramolecular hydrogen bonds are more readily formed in water - they are
entropically more favourable.
O
O
O
OH
H
O
O
H
O
O
-
H
+
-
O
O
O
O
H
+
-
pKa1=1.91 pKa2=6.33
HO2C
CO2H
HO2C
CO2- CO2-
CO2-
H
+
- H
+
-
pKa1=3.03 pKa2=4.54
27. Hydrogen bonding and bioavailability
Remember! Most oral drugs are absorbed through the gut wall by
transcellular absorption.
De-solvation and formation of a neutral molecule is unfavourable if the
compound forms many hydrogen or ionic bonds with water.
So, as a good rule of thumb, you don’t want too many hydrogen bond
donors or acceptors, otherwise the drug won’t get from the gut into the
blood.
There are some exceptions to this – sugars, for example, but these
have special transport mechanisms.
H
O
H H
O
H
H
O
H
H
O
H
O
H
O
H
H
N
N
O
H
O
H
O
O
H O
H
H
H
O
H
O
H
H
N
+
H
H
H
H
O
H
O
H
H
N
N
O
H
O
H
O
O
H
N
H
H
28. Molecular size
Molecular size is one of the most important factors affecting
biological activity, but it’s also one of the most difficult to
measure.
There are various ways of investigating the molecular size,
including measurement of:
Molecular weight (most important)
Electron density
Polar surface area
Van der Waals surface
Molar refractivity
30. Number of rotatable bonds
A rotatable bond is defined as any single non-ring bond,
attached to a non-terminal, non-hydrogen atom. Amide C-N
bonds are not counted because of their high barrier to rotation.
O
OH
N
H
NH2
O
O
OH
N
H
Atenolol
Propranolol
No. of rotatable
bonds
31. Number of rotatable bonds
A rotatable bond is defined as any single non-ring bond,
attached to a non-terminal, non-hydrogen atom. Amide C-N
bonds are not counted because of their high barrier to rotation.
O
OH
N
H
NH2
O
O
OH
N
H
Atenolol
Propranolol
No. of rotatable
bonds
Bioavailability
8
6
50%
90%
The number of rotatable bonds influences, in particular,
bioavailability and binding potency. Why should this be so?
32. Number of rotatable bonds
Remember δG = δH – TδS ! A molecule will have to adopt a fixed
conformation to bind, and to pass through a membrane. This involves a
loss in entropy, so if the molecule is more rigid to start with, less entropy
is lost. But beware!
R
H H
H H
R
H
H
H
H
R
H
H
R
R
H
H
Any, or none, of these could be the active conformation!
33. Solubility, including in human intestinal fluid
Hygroscopicity, i.e. how readily a compound
absorbs water from the atmosphere
Crystalline forms – may have different properties
Chemical stability (not a physical property! Look
at stability to pH, temperature, water, air, etc)
How can these be altered?
Different counter ion or salt
Different method of crystallisation
Bulk physical properties
When a compound is nearing nomination for entry
to clinical trials, we need to look at:
34. This seems like a lot to remember!
There are various guidelines to help, the most well-
known of which is the Lipinski Rule of Five
molecular weight < 500
logP < 5
< 5 H-bond donors (sum of NH and OH)
< 10 H-bond acceptors (sum of N and O)
An additional rule was proposed by Veber
< 10 rotatable bonds
Otherwise absorption and bioavailability are likely to
be poor. NB This is for oral drugs only.
35. The Drug Design Conundrum
logD/Clearance/CYP inhibition
Potency
New receptor interaction
to increase potency and modulate
bulk properties
Find a substitution position not affecting
potency where bulk properties can be
modulated for good DMPK
Trade potency for
DMPK improvements
dose to man focus
The conundrum is that while pharmacokinetic properties improve by
modulating bulk properties, potency also depends on these – particularly
lipophilicity. There are then three approaches that could be adopted.