The Cutting Edge of Chemistry, Apr. - Jun. 2010 -- Pharma Matters Report
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The Cutting Edge of Chemistry, Apr. - Jun. 2010 -- Pharma Matters Report The Cutting Edge of Chemistry, Apr. - Jun. 2010 -- Pharma Matters Report Document Transcript

  • Image CopyrIght: iSTOCKPHOTOTHE CUTTING EDGEOF CHEMISTRYA PHARMA MATTERS REPORT.APRIL - JUNE 2010 NEW! Action-packed chemistry review providing insight into the latest synthesis schemes, scaffolds, mechanisms of action and new structures advancing drug discovery and development.
  • The Cutting Edge of Chemistry discloses new ideas and achievements in the biomedical research field with the chemist’s perspective in mind and is a recently launched addition to the Pharma Matters report series. The report has been organized into sections that delineate essential aspects of the search for better and safer drugs. The Organic Synthesis Scheme Showcase presents a selection of cutting- edge organic syntheses for drugs currently on the market or in development worldwide and described in premier publications in medicinal chemistry as well as in the current patent literature. This section provides access to state-of-the- art synthetic methods for bioactive compounds, as well as demonstrating how new synthetic methods lead to interesting intermediates or drugs. Chemists often start with a novel chemical structure in the drug discovery process. Molecular scaffolds are the building blocks with which they build more sophisticated active compounds. Chemists have so far explored only small regions of the vast molecular universe looking for therapeutic agents, but are constantly pushing back the frontiers. Scaffolds on the Move relates efforts in this arena. Finding new targets to address more selectively is crucial to sustaining a competitive advantage in pharmaceutical research. Indeed, accurate target identification and validation processes in the very early stages of any drug R&D project can make the difference between success and failure in the clinical application of a new drug as well as a strong intellectual property strategy. The New Molecular Mechanisms of Action feature highlights this critical aspect of early-stage research. The Starting Line includes a series of new molecular entities just entering the R&D pipeline. Novel, biologically active molecules picked from the current scientific literature and meetings are revealed in this section. Not surprisingly, these research projects from industry and academia are the culmination of the earlier steps in the process: discovery of an original chemical structure, identification of an appealing new mechanism of action, and determination of synthetic feasibility. Thomson Reuters has widely applied in the design of its products and services the dynamics driving end-user information needs. The Cutting Edge of Chemistry is the most recent addition to this concept and we expect it will constitute, together with the existing Pharma Matters reports, a useful addition to your reading list. IN THIS ISSUE 1 orgaNIC SyNtheSIS SCheme ShoWCaSe An exciting entry to a first-in-class ketolide antibiotic known as EDP-420 has now been scaled up prior to further testing. 4 SCaFFoLDS oN the moVe Rapid screening with silkworm larvae could speed up drug discovery and is this issue’s highlight. Also showcased are leishmaniasis drugs, hypocholesterolemics, and drugs to combat HIV. 7 NeW moLeCULar meChaNISmS oF aCtIoN In this issue, we highlight the mode of action of antimycobacterial agents for tuberculosis with methionine aminopeptidase-1a inhibitory activity and of antidiabetic compounds that are inhibitors of insulin-degrading enzyme. 9 the StartINg LINe aND target FoCUS Biologics are slowly emerging as an interesting and powerful avenue of drug discovery but still represent only a fraction of therapies, both launched and potential, compared to small- molecule organic drugs.PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY A
  • ORGANIC SYNTHESIS SCHEME:COST-EFFECTIVE KETOLIDE ENTRYAn efficient large-scale synthesis of EDP-420, a first-in-classbridged bicyclic ketolide antibiotic drug candidate, offers a cost-effective entry point to these compounds in just ten steps [1].EDP-420 (generic name: modithromycin) is a member of anew class of antibiotics designed by Enanta to circumvent theresistance problems now seen with traditional macrolides,penicillins, and fluoroquinolones, which are often ineffectiveagainst certain strains of respiratory pathogens.EDP-420 is active against Haemophilus influenzae; atypicalorganisms, such as Chlamydia pneumoniae, Mycoplasmapneumoniae, and Legionella pneumophila; and even multidrug-resistant streptococci. Enanta has demonstrated safety andtolerability and presented pharmacokinetics results for thecompound in healthy adults [2], with the conclusion thatefficacy trials for respiratory tract infections should be pursued.EDP-420 is now in phase II clinical trials for the treatment ofcommunity-acquired pneumonia (CAP) [3][4].The ten-step synthesis to EDP-420 begins with inexpensiveand commercially available erythromycin A 9-oxime, which isconverted to the end product using triacetylation, palladium-catalyzed O,O-bis-allylation (bridge formation), acid-catalyzedsugar cleavage, oxime reduction, acetylation, Os-catalyzedbridge olefin oxidative cleavage, Corey-Kim oxidation, bridgeoxime formation, deprotection, and, finally, purification to yieldmulti-kilogram quantities.When scaling up from the discovery stage, two transformationsrequired modification of the reaction conditions. The olefinoxidative cleavage, which had initially been carried out byozonolysis, was finally performed employing sodium periodateand catalytic amounts of osmium tetroxide, conditions thatadapted well to the equipment available at the pilot plant.The ketolide formation was modified to circumvent the use ofDess-Martin periodinane at the multi-kilogram scale, for costand safety reasons. Hence, a screening for alternative reagentsrevealed that the Corey-Kim conditions provided satisfactoryyields and selectivities after a convenient optimization of theNCS stoichiometry.INTEGRITY ENTRY NUMBER: 347484 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 1
  • The ten-step synthesis to EDP-420 begins with Synthesis scheme for EDP-420 (Part 1)inexpensive and commercially available erythromycin H3C CH3 H3C CH3A 9-oxime, which is converted to the end product using N Ntriacetylation, palladium-catalyzed O,O-bis-allylation OH CH3 HO OAc CH3 AcO(bridge formation), acid-catalyzed sugar cleavage, N N CH3 CH3oxime reduction, acetylation, Os-catalyzed bridge olefin H3C O O CH3 H3C O CH3 HO HO Ooxidative cleavage, Corey-Kim oxidation, bridge oxime HO Ac2O, Et3N HO HO HOformation, deprotection, and, finally, purification to H3C CH3 DMAP H3C CH3yield multi-kilogram quantities. O O CH3 O O CH3 O O CH3 CH3 CH3 CH3 O OH O OAc (I) H3C OMe H3C OMe (II) CH2 CH2 Boc2O, NaOH HO OH O O Pd2dba3, dppb Boc Boc reflux Bu4NHSO4 (IV) (III) CH2 CH2 H3C CH3 H3C CH3 N N OH CH3 OAc CH3 AcO AcO N N O H3C O O O H3C O O CH3 O O CH3 H3C H3C HO HO HO H3C CH3 H3C CH3 HCl O CH3 O O O CH3 CH3 CH3 CH3 O O OAc (VI) (V) H3C OMe TiCl3 CH2 H3C CH3 CH2 N CH3 H3C CH3 AcO H3C O N HN CH3 AcO O H3C O O O CH3 N H3C O H3C O HO O O CH3 HO Ac2O H3C H3C CH3 HO HO O H3C CH3 CH3 CH3 O O CH3 CH3 (VII) O (VIII) continues...2 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY
  • Synthesis scheme for EDP-420 (Part 2) continued... CH2 O H3C CH3 N H3C CH3 H3C O N CH3 H3C O AcO CH3 AcO N NO H3C O O O CH3 O H3C O O O CH3 H3C HO H3C HO HO H3C CH3 NaIO4, OsO4 HO H3C CH3 O CH3 CH3 O CH3 CH3 O (VIII) O (IX) NCS, Me2S, Et3N O H3C CH3 H3C O N CH3 AcO N N N N O H3C O O O O CH3 NH2 H3C HO (XI) O H3C CH3 O CH3 CH3 1) HCl O 2) MeOH (X) N N N O N H3C CH3 H3C O N CH3 AcO N O H3C O O O CH3 H3C HO O H3C CH3 O CH3 CH3 O PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 3
  • SCAFFOLDS ON THE MOVE: SILKWORMS AND THE FIGHT AGAINST MRSA Antiinfectives, antidiabetic agents, and antiobesity scaffolds all feature in this edition of The Cutting Edge of Chemistry. A natural product skeleton from a marine source, almiramide, has potential against leishmaniasis, while Yale scientists’ synthetic calixarene derivatives could prove useful in treating HIV. A range of phosphocoumarin analogues are investigated as targeting pancreatic cholesterol esterase, while a skeleton linker modification gives Dainippon Sumitomo Pharma a new lead in regulating low-density lipoprotein. Merck & Co. targets obesity and diabetes with its MCD inhibitors. A group at Kitasato University in Tokyo, Japan, gives us the highlighted skeleton for this issue in the form of the nosokomycins, which are antibiotics with activity against methicillin-resistant Staphylococcus aureus (MRSA). Found to belong to the moenomycin family, they bear the characteristic unusual sesterterpenoid fragment. The team has used a rather novel biological approach to early-stage screening for activity that allowed them to quickly home in on the most active compounds. Rather than using a conventional agar diffusion assay based on paper disks, the team used live silkworm larvae. In vivo studies are plagued with expense and ethical considerations, particularly at the primary discovery stage. The use of invertebrates rather than mammals addresses both considerations to some degree, and researchers have focused on Caenorhabditis elegans (a nematode worm), the fruit fly Drosophila melanogaster, and silkworms. Indeed, the Japanese researchers had previously demonstrated that a model of silkworm larvae infected with human pathogenic bacteria followed by injection with a test compound can reveal whether or not the test substance has antibiotic activity on the basis of survival of the larvae or otherwise [5][6]. “Several companies in Japan are interested in the silkworm assay for evaluating or screening antibiotics,” says team member Hiroshi Tomada, “but it is still at the early stages of development. We believe that this silkworm system is good for predicting antibiotic efficacy in vivo, and reducing the number of animals for drug development.”4 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY
  • FeatUreD SCaFFoLDSILKY APPROACH TO ANTIBIOTICS O NH2Two papers from the Kitasato Institute describe nosokomycins, antibiotics OH O HO CH3 O O CH3 CH2from the broth of Streptomyces sp. K04-0144. They are new members HO OH H2N O O OH P O O H3C CH3 CH3 CH3 CH3of the structurally rare moenomycin family, which bears an unusual HO O O O O O OHsesterterpenoid moiety. Their identity characteristic is the absence of the H3C H N O O OH O NH CH3cyclopentenone ring present in the oligosaccharide moiety of moenomycin O O HO CH3A. The team used a rather new approach to detecting these compounds by HO O Oscreening microbial culture broths with an in vivo-mimic assay employing HO OH OHsilkworm larvae. Activity against MRSA was demonstrated at low doses.THERAPEUTIC GROUP: MOST RECENT SOURCE:Antibiotics Uchida, R.; Iwatsuki, M.; Kim, Y.P.; Ohte, S.; Omura, S.; Tomoda, H. Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. I: Fermentation, isolation and biological properties. J Antibiot 2010, 63(4): 151. Uchida, R.; Iwatsuki, M.; Kim, Y.P.; Omura, S.; Tomoda, H. Nosokomycins, new antibiotics discovered in an in vivo-mimic infection model using silkworm larvae. II: Structure elucidation. J Antibiot 2010, 63(4): 157.ORGANIZATION: INTEGRITY ENTRY NUMBER:Kitasato Institute 466456LIPOPEPTIDE LEAD FOR LEISHMANIASIS H3C CH3The protozoal disease leishmaniasis afflicts 12 million people worldwide CH3 CH3 O CH3 O CH3 CH3 Oeach year and so represents a major target for new scaffolds. U.S. N N N N N NH2 HCresearchers have focused on almiramides A-C, extracted from marine O H3C CH3 CH3 O H3C CH3 CH3 Ocyanobacteria, as they have in vitro activity against the parasite. Thescaffold is an N-methylated linear lipopeptide with an unsaturatedterminus on the side chain that is a requirement for activity. Structure-activity optimization has led to a new compound from which severalsemi-synthetic derivatives with fully methylated peptide backbones andimproved selectivity indices have been obtained.THERAPEUTIC GROUP: MOST RECENT SOURCE:Antileishmanials Sanchez, L.M.; Lopez, D.; Vesely, B.A.; Della Togna, G.; Gerwick, W.H.; Kyle, D.E.; Linington, R.G. Almiramides A-C: Discovery and development of a new class of leishmaniasis lead compounds. J Med Chem 2010, 53(10): 4187.ORGANIZATION: INTEGRITY ENTRY NUMBER:University of California, Santa Cruz 698465INDICASATScripps Institution of OceanographyUniversity of California, San DiegoUniversity of South Florida PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 5
  • NEW LINK FOR CHOLESTEROL-LOWERING COMPOUNDS Dainippon Sumitomo Pharma describes the extension of work with an N N up-regulator of low-density lipoprotein receptor (LDL-R) expression, which is an inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT). N H3C CH3 They have replaced the methylene urea linker in their compound with an H acylsulfonamide linker, which then allowed them to retain potent LDL-R O N O S CH3 up-regulatory activity but reduce interference with ACAT even at O O 1 µM concentration. The sodium salts of the optimized compound reduced CH3 O plasma total and LDL cholesterol levels in a hyperlipidemic animal model. CH3 THERAPEUTIC GROUP: MOST RECENT SOURCE: Treatment of Lipoprotein Disorders Asano, S.; Ban, H.; Tsuboya, N.; Uno, S.; Kino, K.; Ioriya, K.; Kitano, STUDIED MECHANISM OF ACTION: M.; Ueno, Y. LDL-Receptor Up-Regulators A novel class of antihyperlipidemic agents with low density lipoprotein receptor up-regulation via the adaptor protein autosomal recessive hypercholesterolemia. J Med Chem 2010, 53(8): 3284. ORGANIZATION: INTEGRITY ENTRY NUMBER: Dainippon Sumitomo Pharma 697434 PHOSPHOCOUMARINS TARGET CHOLESTEROL ENZYME Cl Pancreatic cholesterol esterase (CEase) is a useful target in atherosclerosis and for the development of hypocholesterolemic agents. A team at Sun Yat-Sen University has prepared 45 isocoumarin phosphorus analogues, O P phosphaisocoumarins, and investigated inhibition of CEase. Three of these O OH phosphaisocoumarins displayed a potent inhibitory effect on Cease, with IC50 values of 4.8, 2.3 and 1.9 µM. THERAPEUTIC GROUP: MOST RECENT SOURCE: Treatment of Disorders of Li, B.; Zhou, B.; Lu, H.; Ma, L.; Peng, A.Y. the Coronary Arteries and Phosphaisocoumarins as a new Atherosclerosis class of potent inhibitors for pancreatic cholesterol esterase. STUDIED MECHANISM OF ACTION: Eur J Med Chem 2010, 45(5): 1955. Cholesterol Esterase Inhibitors ORGANIZATION: INTEGRITY ENTRY NUMBER: Sun Yat-Sen University 696200 MCD INHIBITION KEEPING HUNGER AT BAY F Merck discusses a new class of MCD (malonyl-CoA decarboxylase) H F F N inhibitors with potential in treating type 2 diabetes and obesity, two N CH3 HO S conditions with the biggest risk of chronic disease and mortality. The F N O researchers have focused on the fatty acid intermediate malonyl-CoA F F N because of its role in satiety and the fact that inhibition of MCD in the brain increases levels of the substance. Research in mice has shown inhibition to lead to a reduction in food intake. Moreover, malonyl-CoA is also an endogenous inhibitor of CPT-I, a fatty acid oxidation (FAO) enzyme, and so MCD inhibition may play an additional role in shifting energy metabolism from FAO to glucose oxidation. THERAPEUTIC GROUP: MOST RECENT SOURCE: Antiobesity Drugs; Tang, H.; Yan, Y.; Feng, Z.; De Jesus, Antidiabetic Drugs R.K.; et al. Design and synthesis of a new class STUDIED MECHANISM OF ACTION: of MCD inhibitors with anti-obesity Malonyl-CoA Decarboxylase and anti-diabetic activities. Inhibitors 32nd Natl Med Chem Symp (June 6-9, Minneapolis-St. Paul) 2010, Abst 34. ORGANIZATION: INTEGRITY ENTRY NUMBER: Merck & Co. 6989816 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY
  • MOLECULAR VASE COMBATS HIV O OYale University scientists report that tetrabutoxy-calix[4]arene derivativeshad previously been shown to be useful oncolytic scaffolds, through HO OHinhibition of binding of VEGF and PDGFR to their respective receptors.They now suggest that a modified calixarene might be used as a dual O NHantiviral strategy in treating HIV and hepatitis C. Mode of action is Ocurrently being investigated, but clues regarding structure-activity HOrelationships suggest that interacting head groups may play a key role in H HOthe dual antiviral effect and that maintaining these at the broader rim of N O O O Othe calixarene cone is essential for activity. O O O O N HTHERAPEUTIC GROUP: MOST RECENT SOURCE: OH OHAnti-HIV Agents; Tsou, L.K.; Dutschman, G.E.; Gullen, OAnti-Hepatitis C Virus Drugs E.A.; Telpoukhovskaia, M.; Cheng, Y.C.; Hamilton, A.D. HN O Discovery of a synthetic dual inhibitor of HIV and HCV infection HO OH based on a tetrabutoxy-calix[4] O O arene scaffold. Bioorg Med Chem Lett 2010, 20(7): 2137.ORGANIZATION: INTEGRITY ENTRY NUMBER:Yale University 694442 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 7
  • NEW MOLECULAR MECHANISMS OF ACTIONThe mode of action of any product is key to understanding how to improve on any given design and howto find more potent leads with fewer potential side effects. We notice in the discovery end of the pipelinefor top Pharma companies the therapeutic areas with greatest focus include inflammation, pain, diabetes,obesity, and bacterial infections. In this issue we highlight the mode of action of antimycobacterial agentsfor tuberculosis with methionine aminopeptidase-1a inhibitory activity and of antidiabetic compoundsinvolving inhibitors of insulin-degrading enzyme. O Cl CN CH 3 O S Cl OH O O O S N I H3C N N S N Cl H H3C CH3 S Cl CH3 O N O O CH3 I UbIqUItIN proteIN LIgaSe m. tUberCULoSIS o. VoLVULUS ChItINaSe eNDopLaSmIN (gp96; e3 INhIbItorS methIoNINe oVCht1 INhIbItorS gpr94) INhIbItorS amINopeptIDaSe-1a (metap1a) INhIbItorS; m. tUberCULoSIS methIoNINe amINopeptIDaSe-1b (metap1b) INhIbItorS MAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS: Cancer, Breast Tuberculosis Onchocerciasis Systemic Lupus Erythematosus ORGANIZATION: ORGANIZATION: ORGANIZATION: ORGANIZATION: Cardiff University Johns Hopkins University Scripps Research Institute University of Connecticut Barbara Ann Karmanos School Medicine Korea Res. Inst. Chem. Technol. Cancer Institute Texas Southern University Seoul National University DRUG NAME: Closantel DRUG NAME: GPM-1 INTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER: 694234 495652 689456 691746 N H N N O O O H H HO N N N .HCl N N NH2 N H H O O NH N N NH2 O OH HN H aCtIVIN reCeptor LIke INSULIN-DegraDINg kINaSe 3 (aLk3; bmpr-Ia) eNzyme (INSULySIN; INhIbItorS abeta-DegraDINg proteaSe) INhIbItorS MAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS: Ossification, extraskeletal; Diabetes Colitis; Anemia ORGANIZATION: ORGANIZATION: Massachusetts General Harvard College Hospital Yale University Stemgent Brigham & Women’s Hospital Brigham & Women’s Hospital DRUG NAME: LDN-193189 DRUG NAME: Ii-1 INTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER: 642052 6683898 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY
  • THE STARTING LINE AND TARGETFOCUS: BIOLOGICS MORE PAINFULTHAN ORGANICSThe Starting Line pinpoints new molecular entities (NMEs)ready to progress into the R&D arena. This issue’s focus is onpain and also looks at NMEs for other conditions includingcancer, asthma and trypanosomiasis.Historically, small drug molecules produced using conventionalorganic synthesis techniques have been developed to treatpain. In recent years drugs from biological sources are receivinga growing interest within the pharmaceutical industry.In contrast to conventional drug synthesis, biologics aremanufactured in a living system such as a microorganism,plant, or animal cell, and are being developed by using a varietyof techniques including recombinant DNA expression.Organically synthesized small molecules have been extremelysuccessful, in part due to the well-defined chemical structure.In many cases, the crystal structure of a small molecule dockingwith its protein target can be obtained to reveal the underlyingchemical mechanism of action and to guide modifications thatcan lead to more efficacious analogues. Moreover, chemicalanalysis and characterization of any components and thepurity of a formulation are relatively accessible using standardlaboratory techniques. In contrast, biologics represent amuch more diffuse proposition and so are far more difficultto determine using standard laboratory tests. After all, someof the components of biologic therapies may be unknown,as post-translational modifications of the biologic can oftengenerate minor changes in the drug.Additionally, the living systems used to produce biologicscan be sensitive to minor changes in the conditions of theproduction process, potentially causing the final product todeviate from the known structure significantly and so alteringthe way in which it acts in the body. As such the source andnature of the starting materials, as well as the manufacturingprocess, have to be extremely tightly controlled to ensure thedrug is produced as expected.In the area of pain monoclonal antibodies (MAbs) are anemerging area of therapeutic research still very much in theirinfancy. It is rather telling that within Integrity there are some230 drugs that are under active development for pain in humantrials. Of these, the overwhelming majority are organicallysynthesized molecules, with no more than 5% classified asMAbs. All the latter act as anti-Nerve Growth Factor drugs. PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 9
  • Thus far no MAbs have been successfully launched for pain. In June 2010, the FDA requested that trials of the Pfizer drug tanezumab for treatment of osteoarthritis pain be suspended, following some concerns around the worsening of osteoarthritis after taking the drug. In July 2010 trials of tanezumab were halted for two further indications. This drug is currently in clinical trials for other forms of pain and is being investigated with regards to continuing. If launched this will be the first biotech therapy approved for pain. In this issue of The Cutting Edge of Chemistry we see three new molecular entities for treatment of pain, none of which are biologics and all of which can be chemically synthesized. However, some observers suggest that one of the limiting factors in the development of biologics is mainly regulatory. If there were a smoother route to approval for biologic drugs, would they become more widespread and provide innovative therapies for healthcare? SOURCE DETAILS N ORGANIZATION: University of LITERATURE: CH3 Cl N Dundee; University of Toronto; Frearson, J.A.; Brand, S.; McElroy, H University of York S.P.; et al. H3C N NH N S N-myristoyltransferase inhibitors O O PRODUCT: DDD-85646 N Cl as new leads to treat sleeping CH3 CONDITION: Trypanosomiasis sickness. Nature 2010, 464(7289): 728. MECHANISM OF ACTION: N-Myristoyltransferase Inhibitors INTEGRITY ENTRY NUMBER: 692017 ORGANIZATION: Merck Frosst LITERATURE: Colucci, J.; Boyd, M.; Berthelette, C.; N PRODUCT: MF-766 Chiasson, J.-F.; et al. N O CONDITION: Arthritis; Pain Discovery of H F 4-{1-[({1-[4-(trifluoromethyl) HO MECHANISM OF ACTION: F benzyl]-1H-indol-7-yl}carbonyl) F Prostanoid EP4 Antagonists O amino]cyclopropyl}benzoic acid INTEGRITY ENTRY NUMBER: (MF-766), a highly potent and 638300 selective EP4 antagonist for treating inflammatory pain. Bioorg Med Chem Lett 2010, 20(12): 3760. Boyd, M.; Frosst, M. The discovery highly potent and selective EP4 antagonists for the treatment of inflammatory pain. 32nd Natl Med Chem Symp (June 6-9, Minneapolis-St. Paul) 2010, Abst 35. H H2N N ORGANIZATION: Argolyn LITERATURE: CH3 NH H3C CH3 Bioscience; Medical University of Hughes, F.M.; Shaner, B.E.; May, O O O H H South Carolina L.A.; Zotian, L.; et al. H3C N N N N N OH Identification and functional H H PRODUCT: ABS-212 O O O CH3 characterization of a stable, CH3 CH3 CONDITION: Pain centrally active derivative of the N OH CH3 neurotensin (8-13) fragment as a CH3 INTEGRITY ENTRY NUMBER: potential first-in-class analgesic. 695716 J Med Chem 2010, 53(12): 4623.10 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY
  • SOURCE DETAILS FORGANIZATION: Amira LITERATURE: FPharmaceuticals Stebbins, K.J.; Broadhead, A.R.; F Baccei, C.S.; et al. O NaPRODUCT: AM-206 O Pharmacological blockade of theCONDITION: Asthma; Chronic O DP2 receptor inhibits cigarette O N Nobstructive pulmonary disease smoke-induced inflammation,(COPD); Rhinitis, allergic mucus cell metaplasia, and epithelial CH3 hyperplasia in the mouse lung.MECHANISM OF ACTION: J Pharmacol Exp Ther 2010, 332(3): 764.CRTH2 Receptor Antagonists Broadhead, A.; Stebbins, K.J.; Stock,INTEGRITY ENTRY NUMBER: N.S.; Coate, H.; et al.691897 AM206, a novel CRTH2 selective antagonist, inhibits sneezing and nasal rubs in a mouse allergic rhinitis model. Am J Respir Crit Care Med 2010, 181(Abstracts Issue): A4047.ORGANIZATION: Wyeth LITERATURE:Pharmaceuticals O’Neill, D.J.; Adedoyin, A.; Alfinito, F P.D.; Bray, J.A.; et al.PRODUCT: WYE-103231 N O Discovery of novel selective S .HClCONDITION: Pain; Pain, neuropathic norepinephrine reuptake inhibitors: N O OH 4-[3-aryl-2,2-dioxido-2,1,3- HMECHANISM OF ACTION: N benzothiadiazol-1(3H)-yl]-1- CH3Norepinephrine Reuptake Inhibitors (methylamino)butan-2-ols (WYE-INTEGRITY ENTRY NUMBER: 103231).695259 J Med Chem 2010, 53(11): 4511. O OORGANIZATION: BIAL LITERATURE: N O Kiss, L.E.; Ferreira, H.S.; Torrão, L.; HO Cl N CH3PRODUCT: BIA-9-1067 Bonifácio, M.J.; Palma, P.N.; Soares- NCONDITION: Parkinson’s disease da-Silva, P.; Learmonth, D.A. HO Cl Discovery of a long-acting, O NMECHANISM OF ACTION: CH3 peripherally selective inhibitor ofCOMT Inhibitors catechol-O-methyltransferase.INTEGRITY ENTRY NUMBER: J Med Chem 2010, 53(8): 3396.686182 O HORGANIZATION: Kyowa Hakko Kirin LITERATURE: N Atsumi, T.; Amishiro, N.; Yamamoto, H3C NPRODUCT: K-454 J.; Nakazato, T.; et al. N H3CCONDITION: Cancer Discovery and development of novel H isoindolinone derivatives as JAKMECHANISM OF ACTION: CH3 inhibitors. HOJak2 Inhibitors; Jak3 Inhibitors 239th ACS Natl Meet (March 21-25, CH3INTEGRITY ENTRY NUMBER: San Francisco) 2010, Abst MEDI 149.476783 CH3ORGANIZATION: Nihon University; LITERATURE: N H N N ORoswell Park Cancer Institute Chen, M.; Matsuda, H.; Wang, L.; et al. HN N NH O N O Pretranscriptional regulation of CH3 CH3PRODUCT: GB-1201 O N HN O NH Tgf-beta1 by PI polyamide prevents O H N N N H N OCONDITION: Ulcer, corneal H scarring and accelerates wound N CH3 H3C O N CH3 N CH3 healing of the cornea after exposure O N O H CH3 HMECHANISM OF ACTION: N N N N N O to alkali. H N H N H3CTGFB1 Expression Inhibitors O H3C CH3 N O Mol Ther 2010, 18(3): 519. H HN N CH3 N HINTEGRITY ENTRY NUMBER: O H3C N O690271 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 11
  • SOURCE DETAILS O ORGANIZATION: J-Pharma; LITERATURE: H2N OH Mitsubishi Tanabe Pharma Oda, K.; Hosoda, N.; Endo, H.; et al. Cl L-type amino acid transporter 1 O PRODUCT: KYT-0353 inhibitors inhibit tumor cell growth. N O CONDITION: Cancer Cancer Sci 2010, 101(1): 173. Cl MECHANISM OF ACTION: Drugs Acting on Amino Acid NH2 Transporters INTEGRITY ENTRY NUMBER: 690239 F O O N ORGANIZATION: LITERATURE: F F N OH Johnson & Johnson Rabinowitz, M.H.; Venkatesan, H.; Cl N H N Rosen, M.; Peltier, H.; et al. PRODUCT: JNJ-42041935 Structure based design CONDITION: Anemia and biological evaluation of benzimidazole HIF prolyl MECHANISM OF ACTION: hydroxylase inhibitors for the Hypoxia-Inducible Factor Prolyl treatment of anemia. Hydroxylase Inhibitors 239th ACS Natl Meet (March 21-25, INTEGRITY ENTRY NUMBER: San Francisco) 2010, Abst MEDI 321. 689991 Cole, P.; Vasiliou, S.; Rosa, E.; Fernandez-Forner, D. Medicinal chemistry highlights from the 239th American Chemical Society National Meeting & Exposition. Drugs Fut 2010, 35(6): 503. paIN targetSCape Integrity provides an interactive view of targets and associated drugs across all therapy areas. In this issue we offer a snapshot of the Integrity Targetscape for pain. The monoclonal antibodies in development in the field of pain all act on the nerve growth factor target highlighted here. SOURCE: Pain Targetscape, Thomson Reuters Integrity [July 2010]12 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY
  • aDDItIoNaL reFereNCeS:[1] Xu, G.; Tang, D.; Gai, Y.; Wang, G.; et al. An efficient large- scale synthesis of EDP-420, a first-in-class bridged bicyclic macrolide (BBM) antibiotic drug candidate. Org Process Res Dev 2010, 14(3): 504.[2] Jiang, L.J.; Wang, M.; Or, Y.S. Pharmacokinetics of EDP-420 after ascending single oral doses in healthy adult volunteers. Antimicrob Agents Chemother 2009, 53(5): 1786.[3] Bermudez, L.E.; Motamedi, N.; Chee, C.; Baimukanova, G.; Kolonoski, P.; Inderlied, C.; Aralar, P.; Wang, G.; Phan, L.T.; Young, L.S. EDP-420, a bicyclolide (bridged bicyclic macrolide), is active against Mycobacterium avium. Antimicrob Agents Chemother 2007, 51(5): 1666.[4] Bermudez, L.E.; Motamedi, N.; Kolonoski, P.; Chee, C.; Baimukanova, G.; Bildfell, R.; Wang, G.; Phan, L.T.; Young, L.S. The efficacy of clarithromycin and the bicyclolide EDP- 420 against mycobacterium avium in a mouse model of pulmonary infection. J Infect Dis 2008, 197: 1506.[5] Kaito, C.; Akimitsu, N.; Watanabe, H.; Sekimizu, K. Silkworm larvae as an animal model of bacterial infection pathogenic to humans. Microb Pathog 2002, 32(4): 183.[6] Hamamoto, H.; Kurokawa, K.; Kaito, C.; Kamura, K.; Razanajatovo, I.M.; Kusuhara, H.; Santa, T.; Sekimizu, K. Quantitative evaluation of the therapeutic effects of antibiotics using silkworms infected with human pathogenic microorganisms. Antimicrob Agents Chemother 2004, 48(3): 774. PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 13
  • GET THE LATEST CHEMISTRY INSIGHTS Thomson Reuters IntegritySM combines biology, chemistry and pharmacology information to deliver the latest insights into drug discovery and development. Identify targets of interest that link to related molecular structures, create SAR tables at a click of a button, view the latest structures, scaffolds and synthetic routes emerging from patents, understand mechanisms of action and disease pathways to improve your lead optimization and reduce late-stage attrition. To learn more about how Integrity can eliminate hours of computer research and empower your discovery activities, visit: ABOUT THOMSON REUTERS Thomson Reuters is the leading source of intelligent information for professionals around the world. Our customers are knowledge workers in key sectors of the global economy. We supply them with the intelligent information they need to succeed in fields that are vital to developed and emerging economies such as law, financial services, tax and accounting, healthcare, science and media. Our knowledge and information is essential for drug companies to discover new drugs and get them to market faster, for researchers to find relevant papers and know what’s newly published in their subject, and for businesses to optimize their intellectual property and find competitive intelligence. NOTE TO PRESS: To request further information or permission to reproduce content from this report, please contact: Paul Sandell Phone: + 44 20 7433 4704 Email: To sign up to our Pharma Matters range of publications visit: THE ONES TO WATCH Focuses on the latest phase changes in the pharmaceutical pipeline. MOVERS AND SHAKERS Unravels the most significant game-play in the US generics market. THE CUTTING EDGE OF CHEMISTRY Insights into the chemistry advances transforming drug discovery and development.heaLthCare & SCIeNCeregIoNaL oFFICeSNorth AmericaPhiladelphia +1 800 336 4474 +1 215 386 0100San Diego +1 858 273 8616Latin America +55 11 8370 9845Europe, Middle East and AfricaBarcelona +34 93 459 2220London +44 20 7433 4000Asia PacificSingapore +65 6775 5088Tokyo +81 3 5218 6500For a complete office list © 2010 Thomson Reuters