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

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MEDI 53 Design and synthesis of a series of 7-substituted 2-(4-fluorobenzyl)-9-hydroxy-3,4- dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione inhibitors of HIV-1 Integrase and viral replication in cells Mark W. Embrey 1 , H. Marie Langford 1 , Theresa Booth 2 , Peter Williams 3 , John Wai 1 , Joseph Vacca 1 , Daria J. Hazuda 4 , Michael D. Miller 5 , Peter J. Felock 6 , Kara A. Stillmock 7 , William A. Schleif 8 , Lori J. Gabryelski 5 , Lixia Jin 9 , Joan D. Ellis 10 , and Terry A. Lyle 1 . (1) Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, Fax: 215-652-3971, mark_embrey@merck.com, (2) Department of Medicinal Chemistry, Merck & Co., Inc, Merck Research Laboratories, West Point, PA 19486, (3) Department of Medicinal Chemistry, Merck and Company, West Point, PA 19486, (4) MRL, West Point, PA, USA, Upper Gwynedd, PA 19454-2505, (5) Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, (6) Antiviral Research, Merck and Co. Inc, PO Box 4 West Point, PA 19486-0004, (7) MRL, West Point, PA, USA, West Point, PA 19486, (8) Vaccine and Biologics Research, Merck Research Laboratories West Point, West Point, PA 19486, (9) Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, (10) Drug Metabolism and Pharmaceutical Research, Merck Research Laboratories, West Point, PA 19486 A series of novel bicyclic 2-(4-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine- 1,6,8(7H)-trione HIV-1 integrase inhibitors was designed and synthesized. These compounds selectively inhibit the stand transfer step of integration and are active against HIV-1 in cell culture. Further exploration in this series led to Compound A which exhibits moderate antiviral potency [IC50 250 nM (10% FBS), IC95 813 nM (50% NHS)] and good pharmacokinetics in rat. MEDI 54 Tricyclic 10-hydroxy-7, 8-dihydropyrazinopyrrolopyrazine-1, 9-diones as potent, orally bioavailable HIV-1 integrase strand transfer inhibitors Catherine M. Wiscount 1 , Lekhanh O. Tran 1 , Mark W. Embrey 1 , Thorsten E. Fisher 1 , Vanessa Sherman 1 , Donnette D. Staas 1 , Peter Williams 1 , John Wai 1 , Terry A. Lyle 1 , Joseph Vacca 1 , Peter J. Felock 2 , Marc V. Witmer 2 , Lori Gabryelski 2 , Michael D. Miller 2 , Daria J. Hazuda 3 , Linda Ecto 2 , WA. Schleif 2 , Christopher J. Kochansky 4 , and M. Reza Anari 5 . (1) Department of Medicinal Chemistry, Merck Research Laboratories, WP14-3 Sumneytown Pike, PO Box 4, West Point, PA 19446, Fax: 215-652-3971, cathy_wiscount@merck.com, (2) Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, (3) MRL, West Point, PA, USA, Upper Gwynedd, PA 19454-2505, (4) Drug Metabolism, Merck Research
Laboratories, West Point, PA 19486, (5) Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486 A series of novel tricyclic 10-hydroxy-7, 8-dihydropyrazinopyrrolopyrazine-1, 9-dione HIV-1 integrase strand transfer inhibitors is described. Balancing overall lipophilicity with R group modifications was an important consideration in order to obtain high potency for inhibiting HIV-1 replication in cell culture in the presence of human serum. Excellent pharmacokinetic properties in rats was achieved with several analogs in which R 2 is hydrogen, and small alkyl substituents at R 3 and R 4 provided good activity against a panel of integrase mutants raised in the laboratory with different integrase inhibitors. Synthesis methods and structure-activity relationships for compounds in this structural series will be presented. MEDI 55 Discovery and synthesis of a potent long-acting inhibitor of HIV integrase Debra S. Perlow 1 , Melissa Egbertson 1 , John Wai 1 , Linda S. Payne 1 , Wei Han 1 , Cuthbert D. Martyr 2 , Vanessa E. Obligado 1 , Kristi L. Hoffman 1 , Joseph Vacca 1 , Daria J. Hazuda 3 , Peter J. Felock 4 , Kara A. Stillmock 4 , William A. Schleif 4 , Lori Gabryelski 4 , M. Reza Anari 5 , Joan Ellis 5 , Marc V. Witmer 4 , Michael Miller 4 , Nancy N. Tsou 6 , Mirlinda Biba 6 , Christopher J. Welch 6 , and Terry A. Lyle 1 . (1) Department of Medicinal Chemistry, Merck Research Laboratories, WP14-3, PO Box 4, West Point, PA 19486, Fax: 215-652-3971, debbie_perlow@merck.com, (2) Department of Chemistry, Purdue University, (3) Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, (4) Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, (5) Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, (6) Department of Process Research, Merck Research Laboratories, Rahway, NJ 07065-0900 In the life-cycle of HIV, integration of viral DNA into the host genome is necessary for viral replication to occur. The HIV Integrase enzyme is required in the viral strand transfer step of the integration process (Hazuda et al, Science 2004, 305, 258). Inhibition of the HIV Integrase enzyme step has been shown to inhibit viral replication both in the laboratory and in HIV infected patients. We will describe the discovery and synthesis of Compound A, a potent, longacting tetrahydronaphthyridine inhibitor of HIV Integrase.
Page 1 and 2: Division of Medicinal Chemistry Abs
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 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: The significant antiviral propertie
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
Page 61 and 62: Apoptosis is a process of cell deat
Page 63 and 64: MEDI 120 Novel purine based "atypic
Page 65 and 66: MEDI 124 Efficient removal of ruthe
Page 67 and 68: library approach using technology-e
Page 69 and 70: MEDI 131 Synthesis and biological e
Page 71 and 72: MEDI 135 Identification of AT-1002
Page 73 and 74: Spectroscopic evidence was used to
Page 75 and 76: MEDI 142 Molecular basis for irreve
Page 77 and 78: 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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