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

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esults of clinical studies of Isentress including prospects and future drug discovery efforts in this class of agents. MEDI 3 Tricyclic HIV-1 integrase inhibitors: SAR studies and preclinical evaluations Haolun Jin, Matthew Wright, Sammy Matobo, Michael Mish, Salman Jabri, Rachael Lansdown, Maria Fardis, Ruby Cai, Peter Pyun, Richard Pastor, Laura Schacherer, Manuel Tsiang, Xiaowu Chen, James Chen, and Choung U. Kim, Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404, hjin@gilead.com The first HIV integrase inhibitor that demonstrated the efficacy in clinical trials, L-870810, and the first FDA approved integrase inhibitor, raltegravir, represent a major breakthrough in the battle against HIV infections for AIDS patients, in particular for those who are failing previously available therapies due to multi-drug resistance. In this presentation, we discuss progress in the research of a class of integrase inhibitors designed based on the conformationally constrained scaffold shown in Fig. 1. A number of highly potent inhibitors were identified. The studies of SAR and pharmacokinetic evaluation of lead compounds will be presented. Selected activity data on some of these compounds against a panel of HIV resistant mutants will also be presented. MEDI 4 Naphthyridinone (NTD) integrase inhibitors: Discovery of the clinical candidate S/GSK364735 Brian A. Johns, Department of Medicinal Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, Fax: 919-483-6053, brian.a.johns@gsk.com The discovery of the diketoacid inhibitors of the HIV retroviral integration step nearly ten years ago was a seminal contribution that has served to foster the design and development of various heterocyclic scaffolds with increased drug-like properties. Among these second generation scaffolds is a novel series of orally bioavailable inhibitors of viral replication consisting of the naphthyridinone (NTD) core. The design, discovery and optimization of this series including SAR, DMPK properties, and protein binding will be the topics discussed. The above efforts culminated in the selection of S/GSK364735 for clinical evaluation which resulted in a greater than 2 log reduction in viral load in a Phase 2a study. The work presented herein including the
discovery of S/GSK364735 was a result of a joint research collaboration between GlaxoSmithKline and Shionogi & Co. MEDI 5 A potential second generation HIV-1 integrase strand transfer inhibitor with a high genetic barrier to mutation Wei Han 1 , Melissa Egbertson 1 , John Wai 1 , Debbie S. Perlow 1 , Linda S. Payne 1 , Joseph Vacca 1 , D. Hazuda 2 , Mike Miller 2 , Peter J. Felock 2 , Kara Stillmock 2 , Marc V. Witmer 2 , Lori J. Gabryelski 2 , WA. Schleif 2 , Joan Ellis 3 , M. Reza Anari 3 , and Terry A. Lyle 1 . (1) Department of Medicinal Chemistry, Merck Research Laboratories, WP 14-3, PO Box 4, West Point, PA 19486, Fax: 215-652-3971, melissa_egbertson@merck.com, melissa_egbertson@merck.com, (2) Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, (3) Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486 A series of novel bicyclic 4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1- carboxamide HIV-1 integrase inhibitors was designed and synthesized. Compounds in this series are selective inhibitors of HIV-1 integrase strand transfer. Compound A is a potent inhibitor of HIV-1 replication in cell culture (IC95 in 50% human serum = 38 ± 22 nM, n=77). It demonstrates excellent antiviral potency against a panel of mutant viruses selected in vitro using structurally diverse integrase strand transfer inhibitors and therefore may provide a high genetic barrier against the emergence of resistant mutants. Compound A maintains antiviral activities against mutants identified from clinical studies of Raltegravir and exhibits very good PK profiles in rat and dog. MEDI 6 Models of HIV-1 integrase/DNA complex Chenzhong Liao, Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, NIH, DHHS, Frederick, MD 21702, czliao@helix.nih.gov, and Marc C. Nicklaus, Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Frederick, MD 21702, Fax: 301-846-6033, mn1@helix.nih.gov We present an overview of the approximately ten different models published so far of HIV-1 integrase (IN) complexed with models of the viral DNA and, in some cases, additionally with models of the host DNA. We compare their overall geometries, and contrast them with
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Page 5 and 6: compounds was then performed target
Page 7 and 8: MEDI 13 Potent, brain-penetrant, hy
Page 9 and 10: predominately in the liver, leads t
Page 11 and 12: Candidate Optimization Department,
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
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MEDI 99 Development of novel antica
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MEDI 103 Discovery of N-aryl-9-oxo-
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Compounds that interfere with micro
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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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