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Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311).
Qiao, Jennifer X; Wang, Tammy C; Adam, Leonard P; Chen, Alice Ye A; Taylor, David S; Yang, Richard Z; Zhuang, Shaobin; Sleph, Paul G; Li, Julia P; Li, Danshi; Yin, Xiaohong; Chang, Ming; Chen, Xue-Qing; Shen, Hong; Li, Jianqing; Smith, Daniel; Wu, Dauh-Rurng; Leith, Leslie; Harikrishnan, Lalgudi S; Kamau, Muthoni G; Miller, Michael M; Bilder, Donna; Rampulla, Richard; Li, Yi-Xin; Xu, Carrie; Lawrence, R Michael; Poss, Michael A; Levesque, Paul; Gordon, David A; Huang, Christine S; Finlay, Heather J; Wexler, Ruth R; Salvati, Mark E.
Afiliación
  • Qiao JX; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Wang TC; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Adam LP; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Chen AY; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Taylor DS; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Yang RZ; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Zhuang S; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Sleph PG; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Li JP; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Li D; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Yin X; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Chang M; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Chen XQ; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Shen H; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Li J; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Smith D; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Wu DR; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Leith L; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Harikrishnan LS; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Kamau MG; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Miller MM; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Bilder D; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Rampulla R; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Li YX; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Xu C; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Lawrence RM; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Poss MA; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Levesque P; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Gordon DA; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Huang CS; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Finlay HJ; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Wexler RR; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
  • Salvati ME; Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
J Med Chem ; 58(22): 9010-26, 2015 Nov 25.
Article en En | MEDLINE | ID: mdl-26524347
ABSTRACT
Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Benzamidas / Bencilaminas / Proteínas de Transferencia de Ésteres de Colesterol / Anticolesterolemiantes Límite: Animals / Humans / Male Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Benzamidas / Bencilaminas / Proteínas de Transferencia de Ésteres de Colesterol / Anticolesterolemiantes Límite: Animals / Humans / Male Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2015 Tipo del documento: Article País de afiliación: Estados Unidos