Division of Medicinal Chemistry Abstracts-235th ACS National ...

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MEDI 18 Discovery of MK-7009: A novel macrocyclic HCV NS3/4A protease inhibitor John A. McCauley 1 , Michael T. Rudd 1 , Charles J. McIntyre 1 , Kevin T. Nguyen 1 , Joseph J. Romano 1 , John W. Butcher 1 , M. Katharine Holloway 2 , Bang-Lin Wan 1 , Steven S. Carroll 3 , Jillian M. DiMuzio 3 , Donald J. Graham 3 , Steven W. Ludmerer 3 , Shi-Shan Mao 3 , Mark Stahlhut 3 , Christine Fandozzi 4 , Nicole Trainor 4 , David B. Olsen 3 , Joseph P. Vacca 1 , and Nigel J. Liverton 1 . (1) Department of Medicinal Chemistry, Merck Research Laboratories, WP14-3, West Point, PA 19486, john_mccauley@merck.com, (2) Molecular Systems, Merck Research Laboratories, West Point, PA 19486, (3) Antiviral Research, Merck Research Laboratories, West Point, PA 19486, (4) Drug Metabolism, Merck Research Laboratories, West Point, PA 19486 The hepatitis C virus (HCV) infects an estimated 200 million people worldwide including approximately 4 million people in the U.S. and is the leading cause for liver transplantation. The current standard of care for HCV infection is treatment with pegylated interferon alpha in combination with ribavirin, however, this regimen results in limited efficacy and significant side effects. Efforts toward improved HCV treatment include the development of direct antiviral agents which inhibit key steps in the viral replication process. One such target is the HCV NS3/4A protease. Our interest has been in identifying novel HCV NS3/4A protease inhibitors with good enzyme potency, cellular activity and liver exposure. Toward this goal, initial targets were designed using molecular modeling. The development and optimization of lead compounds along with the profile of clinical candidate MK-7009 will be presented. MEDI 19 Design, synthesis and biological profile of BMS-641988: A novel AR antagonist for the treatment of advanced prostate cancer Mark Salvati 1 , Aaron Balog 2 , Rampulla Richard 1 , Soren Giese 3 , Steven H. Spergel 4 , Andrew J. Nation 5 , Raj N. Misra 6 , Kenneth Leavitt 6 , Soong-Hoon Kim 7 , Hai-Yun Xiao 6 , Weifeng Shan 2 , Greg Vite 8 , Ricardo Attar 9 , Marco Gottardis 10 , Janet Dell Dell 9 , Maria Jure-Kunkel 9 , Jieping Geng 9 , Cheryl Rizzo 9 , Mary Obermeier 11 , Stanley R. Krystek Jr. 12 , Foster William 13 , Thomas Spires Jr. 9 , Carrie Xu 11 , Arvind Mathur 14 , Robert Jeyaseelan 9 , Dan Kukral 9 , Stephanie Powlin 13 , and Xue-Qing Chen 15 . (1) CV Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, 311 Pennington Rocky Hill Rd, Hopewell, NJ 08543, Fax: 609-818-5880, mark.salvati@bms.com, (2) Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, (3) Oncology Chemisrty, Bristol--Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, (4) Lawrenceville Discovery Chemistry, Bristol-Myers Squibb PRI, Princeton, NJ 08543-4000, (5) Department of Chemistry, Columbia University, New York, NY 10027, (6) Discovery Chemistry, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, (7) Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, (8) Discovery Chemistry - Pharmaceutical Research Institute, Bristol-Myers Squibb Co, Princeton, NJ 08543-4000, (9) Oncology Discovery Biology, Bristol-Myers Squibb Pharmaceutical Research and Development, Princeton, NJ 08543-400, (10) Oncology Drug Discovery, Bristol-Myers Squibb Co, Pharmaceutical Research Institute, Princeton, NJ, Princeton, NJ 08543, (11) Pharmaceutical
Candidate Optimization Department, Myers Squibb Pharmaceutical Research and Development, Princeton, NJ 08543, (12) Computer-Assisted Drug Design, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, (13) Discovery Toxicology, Bristol-Myers Squibb Pharmaceutical Research and Development, Princeton, NJ 08543, (14) Chemical Synthesis, Bristol-Myers Squibb Pharmaceutical Research and Development, Princeton, NJ 08543, (15) PHARMACEUTICS, Bristol-Myers Squibb Pharmaceutical Research and Development, Princeton, NJ 08543 Carcinoma of the prostate (CaP) is the 2nd leading cause of cancer related death in men in the United States. Androgen ablation via surgical or chemical castration or by treatment with an antiandrogens is currently the treatment of choice for advanced CaP. Although this therapy initially shows an 80-90% response rate, approximately 50% of patients progress to fatal androgen independent CaP (AI-CaP) after about 18 months of treatment. Recent advances in the field have shown that reactivation of the AR signaling pathway is the root cause for the development of AI-CaP. The identification of the role of the AR in AI-CaP suggests that new agents which act at the level of the AR may be effective in the treatment of this disease. Efforts in our lab have identified a novel and highly potent series of [2.2.1]-oxobicyclo-imide based AR antagonists. Optimization of this series by application of structural based drug design and medicinal chemistry approaches resulted in the identification of BMS-641988 as a development candidate for the treatment of advanced CaP. MEDI 20 Discovery of APD791: A potent and selective 5HT2A inverse-agonist for the treatment of cardiovascular disorders Bradley R. Teegarden, Yifeng Xiong, Sonja Strah-Pleynet, Peter I. Dosa, Honnappa Jayakumar, Jin Sun Choi, Marc Decaire, Martin Casper, Lan Pham, Konrad Feichtinger, Brett Ullman, Katie Elwell, John Adams, Juan Ramirez, William Thomsen, Diane Yuskin, Michael Morgan, Abu Sadeque, Weichao Chen, Paul Maffuid, Hussien Al-Shamma, Graeme Semple, Robert R. Webb, and Daniel Connolly, Arena Pharmaceuticals, Inc, 6166 Nancy Ridge Drive, San Diego, CA 92121 The neurotransmitter, 5-Hydroxytryptamine (5-HT, serotonin), has been shown to have important effects in cardiovascular disease. 5-HT plays a key role in arterial thrombus formation by amplifying platelet aggregation in the presence of other agonists, such as collagen, ADP, epinephrine, and thrombin. In this presentation we will describe the development of a new series of 5HT2A receptor inverse-agonists that inhibit the serotonin-induced amplification of platelet aggregation. An early lead provided in vivo proof of concept in a rat model of vascular injury, bleeding and ex vivo platelet aggregation. In this model, and in contrast to clopidogrel used as a control, we were able to demonstrate a favorable separation of anti-thrombotic activity from increased bleeding time. We will detail the complex, multivariate SAR of this series with respect to receptor activity and selectivity, as well as specific off target activities, resulting in the selection of APD791 for preclinical and clinical development.
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Page 3 and 4: discovery of S/GSK364735 was a resu
Page 5 and 6: compounds was then performed target
Page 7 and 8: MEDI 13 Potent, brain-penetrant, hy
Page 9: predominately in the liver, leads t
Page 13 and 14: acceptor atoms as the core componen
Page 15 and 16: Prostaglandin (PG) D 2 is an allerg
Page 17 and 18: polymerization, as described, by pr
Page 19 and 20: MEDI 34 Pyrogallol and its analogs
Page 21 and 22: Nicos A. Petasis 1 , Jasim Uddin 1
Page 23 and 24: Yong-Gil Kim, Joon Heo, Mi-Kyung Ji
Page 25 and 26: A new class of potent NK1 receptor
Page 27 and 28: The significant antiviral propertie
Page 29 and 30: Laboratories, West Point, PA 19486,
Page 31 and 32: MEDI 58 Preparation and antiviral a
Page 33 and 34: MEDI 62 Caco-2 cell based assay dev
Page 35 and 36: FMS-like tyrosine kinase 3 (FLT3) r
Page 37 and 38: MEDI 70 Synthesis of bisphosphonate
Page 39 and 40: ing. These observations suggest a p
Page 41 and 42: MEDI 77 Probing the structure-activ
Page 43 and 44: B-Raf kinase plays a critical role
Page 45 and 46: Gal-CS was used to prepare nanopart
Page 47 and 48: MEDI 88 Trifluoromethyl substituted
Page 49 and 50: MEDI 92 Discovery of novel small mo
Page 51 and 52: MEDI 96 Synthesis and antiprolifera
Page 53 and 54: MEDI 99 Development of novel antica
Page 55 and 56: MEDI 103 Discovery of N-aryl-9-oxo-
Page 57 and 58: Compounds that interfere with micro
Page 59 and 60: Carbonyl reductase (CR) has been im
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Apoptosis is a process of cell deat
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MEDI 120 Novel purine based "atypic
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MEDI 124 Efficient removal of ruthe
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library approach using technology-e
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MEDI 131 Synthesis and biological e
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MEDI 135 Identification of AT-1002
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Spectroscopic evidence was used to
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MEDI 142 Molecular basis for irreve
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MEDI 146 Effect of fluorine on subs
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MEDI 151 Overview of newer approach
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MEDI 156 Defining structure-activit
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MEDI 160 Bivalent inhibitors of P-g
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MEDI 164 Molecular basis for effica
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MEDI 167 Discovery of the highly po
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highly asymmetric, closely packed d
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4/WP14-3, Sumneytown Pike, West Poi
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MEDI 179 Design, synthesis, and eva
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MEDI 182 Substituted-pyrrole 2-amin
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MEDI 186 Discovery and optimization
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phosphatase SHIP. Bioassay guided f
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epibatidine for nicotinic channels.
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derivative with striking solubility
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MEDI 203 Core-modified mannopeptimy
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MEDI 207 Enhancing the kinetic prof
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hydroxyphenyl)piperazin-1-yl)butyl)
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migration of people from these area
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Schistosomiasis is, after malaria,
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-Ketoacyl-ACP-synthase III (FabH) h
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MEDI 225 Synthesis of the analog of
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MEDI 229 Structure-based virtual sc
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MEDI 234 TG100801: A prodrug for th
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In the past, large collections of c
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approach to the treatment of autoim
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logPe values. The residual mean squ
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Oligo-chitosan (OCS) which is a kin
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characterization of novel muscarini
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MEDI 257 Rigid analogs of 4,4-diary
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MEDI 261 Strategies toward improvin
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disease. It is generally accepted t
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(BBB). Our preliminary in vitro dat
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It is well-documented that androgen
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MEDI 276 Investigating the manipula
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were screened by FACS sarin labeled
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MEDI 285 Design, synthesis and biol
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equipment set-up and large scale ma
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Significant effort has been directe
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esearch was supported by funds from
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synthesized a series of carbamoylch
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proceeded more rapidly by switching
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genes. With the understanding of th
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MEDI 310 Optimized methods for the
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Coupled with crystallographic data,
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MEDI 317 Design and synthesis of hy
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MEDI 320 Synthesis and antibacteria
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DTPA. Incorporation of the nitro fu
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MEDI 328 The mechanism of bioreduct
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esistance, there is an urgent need
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Giving the Rule-of-5 a more accurat
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MEDI 338 Structure guided design of
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MEDI 342 Synthesis of peptide-amilo
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MEDI 346 Design, synthesis, and ant
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