the cutting edge of chemistry, apr. - jun. 2010 -- pharma matters report

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 CHEMISTRYA PHARMA MATTERS REPORT.APRIL - JUNE 2010

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http://www.thomsonreuters.com

A PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

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 ISSUE1 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 moVeRapid 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 aCtIoNIn 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 FoCUSBiologics 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 1

ORGANIC SYNTHESIS SCHEME: COST-EFFECTIVE KETOLIDE ENTRYAn efficient large-scale synthesis of EDP-420, a first-in-class bridged 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 a new class of antibiotics designed by Enanta to circumvent the resistance problems now seen with traditional macrolides, penicillins, and fluoroquinolones, which are often ineffective against certain strains of respiratory pathogens.

EDP-420 is active against Haemophilus influenzae; atypical organisms, such as Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila; and even multidrug-resistant streptococci. Enanta has demonstrated safety and tolerability and presented pharmacokinetics results for the compound in healthy adults [2], with the conclusion that efficacy trials for respiratory tract infections should be pursued. EDP-420 is now in phase II clinical trials for the treatment of community-acquired pneumonia (CAP) [3][4].

The ten-step synthesis to EDP-420 begins with inexpensive and commercially available erythromycin A 9-oxime, which is converted to the end product using triacetylation, palladium-catalyzed O,O-bis-allylation (bridge formation), acid-catalyzed sugar cleavage, oxime reduction, acetylation, Os-catalyzed bridge olefin oxidative cleavage, Corey-Kim oxidation, bridge oxime formation, deprotection, and, finally, purification to yield multi-kilogram quantities.

When scaling up from the discovery stage, two transformations required modification of the reaction conditions. The olefin oxidative cleavage, which had initially been carried out by ozonolysis, was finally performed employing sodium periodate and catalytic amounts of osmium tetroxide, conditions that adapted well to the equipment available at the pilot plant.

The ketolide formation was modified to circumvent the use of Dess-Martin periodinane at the multi-kilogram scale, for cost and safety reasons. Hence, a screening for alternative reagents revealed that the Corey-Kim conditions provided satisfactory yields and selectivities after a convenient optimization of the NCS stoichiometry.INTEGRITY ENTRY NUMBER: 347484

http://integrity.prous.com/integrity/xmlxsl/pk_prod_list.xml_prod_list_card_pr?p_id=347484

2 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

Synthesis scheme for EDP-420 (Part 1)

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The ten-step synthesis to EDP-420 begins with inexpensive and commercially available erythromycin A 9-oxime, which is converted to the end product using triacetylation, palladium-catalyzed O,O-bis-allylation (bridge formation), acid-catalyzed sugar cleavage, oxime reduction, acetylation, Os-catalyzed bridge olefin oxidative cleavage, Corey-Kim oxidation, bridge oxime formation, deprotection, and, finally, purification to yield multi-kilogram quantities.


Synthesis scheme for EDP-420 (Part 2)

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SCAFFOLDS ON THE MOVE: SILKWORMS AND THE FIGHT AGAINST MRSAAntiinfectives, 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.”


FeatUreD SCaFFoLD

SILKY APPROACH TO ANTIBIOTICSTwo papers from the Kitasato Institute describe nosokomycins, antibiotics from the broth of Streptomyces sp. K04-0144. They are new members of the structurally rare moenomycin family, which bears an unusual sesterterpenoid moiety. Their identity characteristic is the absence of the cyclopentenone ring present in the oligosaccharide moiety of moenomycin A. The team used a rather new approach to detecting these compounds by screening microbial culture broths with an in vivo-mimic assay employing silkworm larvae. Activity against MRSA was demonstrated at low doses.

THERAPEUTIC GROUP: Antibiotics

MOST RECENT SOURCE: 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: Kitasato Institute

INTEGRITY ENTRY NUMBER: 466456

LIPOPEPTIDE LEAD FOR LEISHMANIASISThe protozoal disease leishmaniasis afflicts 12 million people worldwide each year and so represents a major target for new scaffolds. U.S. researchers have focused on almiramides A-C, extracted from marine cyanobacteria, as they have in vitro activity against the parasite. The scaffold is an N-methylated linear lipopeptide with an unsaturated terminus on the side chain that is a requirement for activity. Structure-activity optimization has led to a new compound from which several semi-synthetic derivatives with fully methylated peptide backbones and improved selectivity indices have been obtained.

THERAPEUTIC GROUP: Antileishmanials

MOST RECENT SOURCE: 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: University of California, Santa Cruz

INDICASAT

Scripps Institution of Oceanography

University of California, San Diego

University of South Florida


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NEW LINK FOR CHOLESTEROL-LOWERING COMPOUNDSDainippon Sumitomo Pharma describes the extension of work with an up-regulator of low-density lipoprotein receptor (LDL-R) expression, which is an inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT). They have replaced the methylene urea linker in their compound with an acylsulfonamide linker, which then allowed them to retain potent LDL-R up-regulatory activity but reduce interference with ACAT even at 1 µM concentration. The sodium salts of the optimized compound reduced plasma total and LDL cholesterol levels in a hyperlipidemic animal model.

THERAPEUTIC GROUP: Treatment of Lipoprotein Disorders

STUDIED MECHANISM OF ACTION: LDL-Receptor Up-Regulators

MOST RECENT SOURCE: Asano, S.; Ban, H.; Tsuboya, N.; Uno, S.; Kino, K.; Ioriya, K.; Kitano, M.; Ueno, Y.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: Dainippon Sumitomo Pharma


PHOSPHOCOUMARINS TARGET CHOLESTEROL ENZYMEPancreatic 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, phosphaisocoumarins, and investigated inhibition of CEase. Three of these phosphaisocoumarins displayed a potent inhibitory effect on Cease, with IC50 values of 4.8, 2.3 and 1.9 µM.

THERAPEUTIC GROUP: Treatment of Disorders of the Coronary Arteries and Atherosclerosis

STUDIED MECHANISM OF ACTION: Cholesterol Esterase Inhibitors

MOST RECENT SOURCE: Li, B.; Zhou, B.; Lu, H.; Ma, L.; Peng, A.Y.Phosphaisocoumarins as a new class of potent inhibitors for pancreatic cholesterol esterase.Eur J Med Chem 2010, 45(5): 1955.

ORGANIZATION: Sun Yat-Sen University


MCD INHIBITION KEEPING HUNGER AT BAYMerck discusses a new class of MCD (malonyl-CoA decarboxylase) inhibitors with potential in treating type 2 diabetes and obesity, two conditions with the biggest risk of chronic disease and mortality. The researchers have focused on the fatty acid intermediate malonyl-CoA 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: Antiobesity Drugs; Antidiabetic Drugs

STUDIED MECHANISM OF ACTION: Malonyl-CoA Decarboxylase Inhibitors

MOST RECENT SOURCE: Tang, H.; Yan, Y.; Feng, Z.; De Jesus, R.K.; et al.Design and synthesis of a new class of MCD inhibitors with anti-obesity and anti-diabetic activities.32nd Natl Med Chem Symp (June 6-9, Minneapolis-St. Paul) 2010, Abst 34.

ORGANIZATION: Merck & Co.


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MOLECULAR VASE COMBATS HIVYale University scientists report that tetrabutoxy-calix[4]arene derivatives had previously been shown to be useful oncolytic scaffolds, through inhibition of binding of VEGF and PDGFR to their respective receptors. They now suggest that a modified calixarene might be used as a dual antiviral strategy in treating HIV and hepatitis C. Mode of action is currently being investigated, but clues regarding structure-activity relationships suggest that interacting head groups may play a key role in the dual antiviral effect and that maintaining these at the broader rim of the calixarene cone is essential for activity.

THERAPEUTIC GROUP: Anti-HIV Agents;Anti-Hepatitis C Virus Drugs

MOST RECENT SOURCE: Tsou, L.K.; Dutschman, G.E.; Gullen, E.A.; Telpoukhovskaia, M.; Cheng, Y.C.; Hamilton, A.D.Discovery of a synthetic dual inhibitor of HIV and HCV infection based on a tetrabutoxy-calix[4]arene scaffold.Bioorg Med Chem Lett 2010, 20(7): 2137.

ORGANIZATION: Yale University


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NEW MOLECULAR MECHANISMS OF ACTIONThe mode of action of any product is key to understanding how to improve on any given design and how to find more potent leads with fewer potential side effects. We notice in the discovery end of the pipeline for 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 agents for tuberculosis with methionine aminopeptidase-1a inhibitory activity and of antidiabetic compounds involving inhibitors of insulin-degrading enzyme.

UbIqUItIN proteIN LIgaSe e3 INhIbItorS

m. tUberCULoSIS methIoNINe amINopeptIDaSe-1a (metap1a) INhIbItorS; m. tUberCULoSIS methIoNINe amINopeptIDaSe-1b (metap1b) INhIbItorS

o. VoLVULUS ChItINaSe oVCht1 INhIbItorS

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MAIN RELATED CONDITIONS: Cancer, Breast

MAIN RELATED CONDITIONS: Tuberculosis

MAIN RELATED CONDITIONS: Onchocerciasis

MAIN RELATED CONDITIONS: Systemic Lupus Erythematosus

ORGANIZATION: Cardiff UniversityBarbara Ann Karmanos Cancer Institute

ORGANIZATION: Johns Hopkins University School MedicineTexas Southern University

ORGANIZATION: Scripps Research Institute

ORGANIZATION: University of ConnecticutKorea Res. Inst. Chem. Technol.Seoul National University

DRUG NAME: Closantel DRUG NAME: GPM-1





aCtIVIN reCeptor LIke kINaSe 3 (aLk3; bmpr-Ia) INhIbItorS

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MAIN RELATED CONDITIONS: Ossification, extraskeletal; Colitis; Anemia

MAIN RELATED CONDITIONS: Diabetes

ORGANIZATION: Massachusetts General HospitalStemgentBrigham & Women’s Hospital

ORGANIZATION: Harvard CollegeYale UniversityBrigham & Women’s Hospital

DRUG NAME: LDN-193189 DRUG NAME: Ii-1



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THE STARTING LINE AND TARGET FOCUS: BIOLOGICS MORE PAINFUL THAN ORGANICSThe Starting Line pinpoints new molecular entities (NMEs) ready to progress into the R&D arena. This issue’s focus is on pain and also looks at NMEs for other conditions including cancer, asthma and trypanosomiasis.

Historically, small drug molecules produced using conventional organic synthesis techniques have been developed to treat pain. In recent years drugs from biological sources are receiving a growing interest within the pharmaceutical industry. In contrast to conventional drug synthesis, biologics are manufactured in a living system such as a microorganism, plant, or animal cell, and are being developed by using a variety of techniques including recombinant DNA expression.

Organically synthesized small molecules have been extremely successful, in part due to the well-defined chemical structure. In many cases, the crystal structure of a small molecule docking with its protein target can be obtained to reveal the underlying chemical mechanism of action and to guide modifications that can lead to more efficacious analogues. Moreover, chemical analysis and characterization of any components and the purity of a formulation are relatively accessible using standard laboratory techniques. In contrast, biologics represent a much more diffuse proposition and so are far more difficult to determine using standard laboratory tests. After all, some of the components of biologic therapies may be unknown, as post-translational modifications of the biologic can often generate minor changes in the drug.

Additionally, the living systems used to produce biologics can be sensitive to minor changes in the conditions of the production process, potentially causing the final product to deviate from the known structure significantly and so altering the way in which it acts in the body. As such the source and nature of the starting materials, as well as the manufacturing process, have to be extremely tightly controlled to ensure the drug is produced as expected.

In the area of pain monoclonal antibodies (MAbs) are an emerging area of therapeutic research still very much in their infancy. It is rather telling that within Integrity there are some 230 drugs that are under active development for pain in human trials. Of these, the overwhelming majority are organically synthesized molecules, with no more than 5% classified as MAbs. All the latter act as anti-Nerve Growth Factor drugs.


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 ORGANIZATION: University of Dundee; University of Toronto; University of York

PRODUCT: DDD-85646

CONDITION: Trypanosomiasis

MECHANISM OF ACTION: N-Myristoyltransferase Inhibitors


LITERATURE: Frearson, J.A.; Brand, S.; McElroy, S.P.; et al.N-myristoyltransferase inhibitors as new leads to treat sleeping sickness.Nature 2010, 464(7289): 728.

ORGANIZATION: Merck Frosst

PRODUCT: MF-766

CONDITION: Arthritis; Pain

MECHANISM OF ACTION: Prostanoid EP4 Antagonists


LITERATURE: Colucci, J.; Boyd, M.; Berthelette, C.; Chiasson, J.-F.; et al.Discovery of 4-{1-[({1-[4-(trifluoromethyl)benzyl]-1H-indol-7-yl}carbonyl) amino]cyclopropyl}benzoic acid (MF-766), a highly potent and 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.

ORGANIZATION: Argolyn Bioscience; Medical University of South Carolina

PRODUCT: ABS-212

CONDITION: Pain


LITERATURE: Hughes, F.M.; Shaner, B.E.; May, L.A.; Zotian, L.; et al.Identification and functional characterization of a stable, centrally active derivative of the neurotensin (8-13) fragment as a potential first-in-class analgesic.J Med Chem 2010, 53(12): 4623.

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SOURCE DETAILS ORGANIZATION: Amira Pharmaceuticals

PRODUCT: AM-206

CONDITION: Asthma; Chronic obstructive pulmonary disease (COPD); Rhinitis, allergic

MECHANISM OF ACTION:CRTH2 Receptor Antagonists


LITERATURE: Stebbins, K.J.; Broadhead, A.R.; Baccei, C.S.; et al.Pharmacological blockade of the DP2 receptor inhibits cigarette smoke-induced inflammation, mucus cell metaplasia, and epithelial hyperplasia in the mouse lung.J Pharmacol Exp Ther 2010, 332(3): 764.

Broadhead, A.; Stebbins, K.J.; Stock, N.S.; Coate, H.; et al.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 Pharmaceuticals

PRODUCT: WYE-103231

CONDITION: Pain; Pain, neuropathic

MECHANISM OF ACTION:Norepinephrine Reuptake Inhibitors


LITERATURE: O’Neill, D.J.; Adedoyin, A.; Alfinito, P.D.; Bray, J.A.; et al.Discovery of novel selective norepinephrine reuptake inhibitors: 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231).J Med Chem 2010, 53(11): 4511.

ORGANIZATION: BIAL

PRODUCT: BIA-9-1067

CONDITION: Parkinson’s disease

MECHANISM OF ACTION:COMT Inhibitors


LITERATURE: Kiss, L.E.; Ferreira, H.S.; Torrão, L.; Bonifácio, M.J.; Palma, P.N.; Soares-da-Silva, P.; Learmonth, D.A.Discovery of a long-acting, peripherally selective inhibitor of catechol-O-methyltransferase.J Med Chem 2010, 53(8): 3396.

ORGANIZATION: Kyowa Hakko Kirin

PRODUCT: K-454

CONDITION: Cancer

MECHANISM OF ACTION:Jak2 Inhibitors; Jak3 Inhibitors


LITERATURE: Atsumi, T.; Amishiro, N.; Yamamoto, J.; Nakazato, T.; et al.Discovery and development of novel isoindolinone derivatives as JAK inhibitors.239th ACS Natl Meet (March 21-25, San Francisco) 2010, Abst MEDI 149.

ORGANIZATION: Nihon University; Roswell Park Cancer Institute

PRODUCT: GB-1201

CONDITION: Ulcer, corneal

MECHANISM OF ACTION:TGFB1 Expression Inhibitors


LITERATURE: Chen, M.; Matsuda, H.; Wang, L.; et al.Pretranscriptional regulation of Tgf-beta1 by PI polyamide prevents scarring and accelerates wound healing of the cornea after exposure to alkali.Mol Ther 2010, 18(3): 519.

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SOURCE DETAILS ORGANIZATION: J-Pharma; Mitsubishi Tanabe Pharma

PRODUCT: KYT-0353

CONDITION: Cancer

MECHANISM OF ACTION:Drugs Acting on Amino Acid Transporters


LITERATURE: Oda, K.; Hosoda, N.; Endo, H.; et al.L-type amino acid transporter 1 inhibitors inhibit tumor cell growth.Cancer Sci 2010, 101(1): 173.

ORGANIZATION: Johnson & Johnson

PRODUCT: JNJ-42041935

CONDITION: Anemia

MECHANISM OF ACTION:Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors


LITERATURE: Rabinowitz, M.H.; Venkatesan, H.; Rosen, M.; Peltier, H.; et al.Structure based design and biological evaluation of benzimidazole HIF prolyl hydroxylase inhibitors for the treatment of anemia.239th ACS Natl Meet (March 21-25, San Francisco) 2010, Abst MEDI 321.

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]

NH2

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ON

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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.

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the cutting edge of chemistry, apr. - jun. 2010 -- pharma matters report

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