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

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next-generation inhibitor binds with sub-nanomolar affinities to multiple anti-apoptotic Bcl-2 family proteins. ABT-263 is efficacious in several xenograft models, and is orally bioavailable. MEDI 79 Identification of pyrazolo[1,5-a]pyrimidine-3-carboxylates as B-Raf kinase inhibitors: Part 1 Ariamala Gopalsamy 1 , Gregory M. Ciszewski 1 , Yongbo Hu 1 , Frederick Lee 1 , Larry Feldberg 2 , Eileen Frommer 2 , Steven Kim 2 , Karen Collins 2 , Donald Wojciechowicz 2 , and Robert Mallon 2 . (1) Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, (2) Oncology Research, Wyeth Research, Pearl River, NY 10965 Raf kinases play central role in cell growth and survival and are components of Raf-MEK-ERK signaling pathway. Of the three Raf isoforms, activating B-Raf mutations have been found in 66% of malignant melanomas and in a smaller fraction of other cancers including those of the colorectum. B-Raf mutations in these cancers were found in a systematic genome-wide screening effort to detect alterations in genes that control cell proliferation, differentiation, and death (Davies H, et al. 2002, Nature 417:906). Inhibitors of B-Raf could be used in the treatment of colorectal cancer, melanomas, and other Ras related human cancers. To identify B-Raf inhibitors we established an HTS assay to monitor the kinase activity of both wt and mutant (V600E) forms of this protein. From this effort pyrazolo[1,5-a]pyrimidine-3-carboxylate (1) was identified as a promising B-Raf kinase inhibitor. Expansion of this scaffold class to improve the potency and gather structure activity relationship will be discussed in detail. MEDI 80 Phenylpyrazolo[1,5-a]pyrimidines as B-Raf Inhibitors: Optimization of phenyl group: Part 2 Gregory M. Ciszewski 1 , Ariamala Gopalsamy 1 , Jeremy I. Levin 1 , Kyung-Hee Kim 1 , Yongbo Hu 1 , Frederick Lee 1 , Larry Feldberg 2 , Eileen Frommer 2 , Steven Kim 2 , Karen Collins 2 , Donald Wojciechowicz 2 , and Robert Mallon 2 . (1) Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, Fax: 845-602-3045, ciszewg@wyeth.com, (2) Oncology Research, Wyeth Research, Pearl River, NY 10965
B-Raf kinase plays a critical role in the Raf-MEK-ERK signaling pathway and is a compelling target for cancer chemotherapeutics. From our high throughput screening effort, ethyl 7-(3-(3- (trifluoromethyl)benzamido)-phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate was identified as a hit for inhibition of B-Raf kinase. While a number of regions of the molecule can be varied to explore the possibilities of improving the potency, the central phenyl group was chosen as a means to explore the electronic effects on the structure activity relationship still maintaining low molecular weight. Synthetic efforts to generate the analogs and the observed SAR will be discussed in detail. MEDI 81 Phenylpyrazolo[1,5-a]pyrimidines as B-Raf Inhibitors: Optimization of pyrazolopyrimidne ring substituents: Part 3 Mengxiao Shi 1 , Ariamala Gopalsamy 1 , Dan M. Berger 1 , Minu Dutia 1 , Yongbo Hu 1 , Frederick Lee 1 , Larry Feldberg 2 , Eileen Frommer 2 , Steven Kim 2 , Karen Collins 2 , Donald Wojciechowicz 2 , and Robert Mallon 2 . (1) Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, Fax: 845-602-3045, shim2@wyeth.com, (2) Oncology Research, Wyeth Research, Pearl River, NY 10965 In continuation of our efforts to optimize the B-Raf kinase high throughput screen hit ethyl 7-(3- (3-(trifluoromethyl)benzamido)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate, we explored the importance and the position of the carboxylate moiety. Moving the carboxylate to the adjacent carbon at the 2-position decreased the activity significantly. However, our efforts to replace the labile ester in the 2-position with other ring systems including a number of heterocycles improved the potency significantly. The various analogs generated and the observed structure activity relationship for this region will be disclosed in detail.
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 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: MEDI 77 Probing the structure-activ
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
Page 79 and 80: MEDI 151 Overview of newer approach
Page 81 and 82: MEDI 156 Defining structure-activit
Page 83 and 84: MEDI 160 Bivalent inhibitors of P-g
Page 85 and 86: MEDI 164 Molecular basis for effica
Page 87 and 88: MEDI 167 Discovery of the highly po
Page 89 and 90: highly asymmetric, closely packed d
Page 91 and 92: 4/WP14-3, Sumneytown Pike, West Poi
Page 93 and 94:
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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