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

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MEDI 45 Discovery and SAR of highly selective 5-HT 2A receptor subtype inverse-agonists for inhibition of platelet aggregation Yifeng Xiong, Bradley R. Teegarden, Jin Sun Choi, Sonja Strah-Pleynet, Marc Decaire, Honnappa Jayakumar, Peter I. Dosa, Martin Casper, Lan Pham, Konrad Feichtinger, Brett Ullman, John Adams, Juan Ramirez, William Thomsen, Diane Yuskin, Michael Morgan, Abu Sadeque, Weichao Chen, Hussien Al-Shamma, Graeme Semple, Robert R. Webb, and Daniel Connolly, Arena Pharmaceuticals, Inc, 6166 Nancy Ridge Drive, San Diego, CA 92121, yxiong@arenapharm.com 5-HT 2A receptor inverse-agonists have been proposed to be useful for the treatment of CNS disorders such as schizophrenia, depression, anxiety and insomnia. In addition, peripherally restricted 5-HT 2A inverse-agonists have potential for the treatment of arterial thrombotic disease by inhibiting platelet aggregation. We have identified a series of potent and highly selective pyrazole derivatives that have potent platelet inhibition properties. The design and SAR of these compounds will be discussed. MEDI 46 Targeting serotonin transporter channel activity aids in the development of therapeutic drugs for clinical depression Uyen M. Le 1 , Hideki Iwamoto 1 , Hongping Yuan 1 , Lou DeFelice 2 , and Craig W Lindsley 1 . (1) Department of Pharmacology, Vanderbilt University Medical Center, 2222 23rd @ Pierce Ave., 802 Robinson Research Building, Nashville, TN 37232, uyen.m.le@vanderbilt.edu, (2) Department of Pharmacology and Center for Molecular Neuroscience, Vanderbilt University Clinical depression is a psychiatric disorder characterized by a decrease in serotonin levels. Current antidepressants, such as fluoxetin, act by blocking the serotonin transporter channel preventing the influx of serotonin into the post-synaptic neuron therefore increasing the level of serotonin in the synapse alleviating the symptoms of depression. This project focuses on the development of compounds that target the channel activity of serotonin transporter. This targeting mechanism increases the resting potential of pre-synaptic neuron enhancing the likelihood of action potential to release serotonin by the natural mechanism of vesicle diffusion. MEDI 47 Tetrahydroindolizinone NK1 antagonists: SAR at 7-position Jianming Bao 1 , Huagang Lu 1 , Gregori J. Morriello 1 , Emma Carlson 2 , Richard Tschirret-Guth 3 , Gary G. Chicchi 4 , Marc Kurtz 4 , Kwei-lan Tsao 4 , Song Zheng 3 , Xinchun Tong 3 , Sander Mills 1 , and Robert DeVita 1 . (1) Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, Fax: 732-594-5350, bao_jianming@merck.com, (2) The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow CM20 2QR, United Kingdom, (3) Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, (4) Immunology, Merck Research Laboratories, Rahway, NJ 07065
A new class of potent NK1 receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activity as compared to previous 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core will be presented. A number of compounds displayed high NK1 receptor occupancy at both 1h and 24h in a gerbil foot tapping model. One of these compounds with high NK1 binding affinity, excellent selectivity for other NK receptors and promising in vivo properties will be discussed in detail. MEDI 48 Tuning affinity on a tropane framework for dopamine D2/D3 receptor subtype ligands Noel M. Paul 1 , Christina Z. Floresca 2 , Michelle Taylor 2 , Robert R. Luedtke 2 , Jeffrey R. Deschamps 3 , and Amy H. Newman 1 . (1) Medicinal Chemistry Section, National Institute on Drug Abuse - Intramural Research Program, 333 Cassell Dr, Baltimore, MD 21224, pauln@mail.nih.gov, (2) Department of Pharmacology and Neuroscience, University of North Texas, Health Science Center, Forth Worth, TX 76107, (3) Naval Research Laboratory, Code 6030, Washington, DC 20375 The dopamine D2-like receptor family is comprised of the D2, D3 and D4 subtypes and discovering subtype-selective ligands with which to differentiate the roles of these potentially drugable targets in neuropsychiatric disorders and drug addiction has been a focus of recent investigation. The D2-selective antagonist L741,626 provided a lead template for chemical modification, and a variety of analogues were synthesized wherein the central piperidine ring was replaced by a bicyclic tropane ring system. Overall, these bicyclic compounds displayed structure-activity relationships quite different from those derived in the analogous piperidine series. X-Ray crystallographic data revealed differences in the spatial arrangement of pharmacophoric elements in the piperidine v. tropane-ring analogues that resulted in compounds with subnanomolar affinities for the D2 and D3 receptor subtypes.
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: Yong-Gil Kim, Joon Heo, Mi-Kyung Ji
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
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
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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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