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Discovery of a Lead Triphenylethanamine Cholesterol Ester Transfer Protein (CETP) Inhibitor.
Finlay, Heather J; Jiang, Ji; Rampulla, Richard; Salvati, Mark E; Qiao, Jennifer X; Wang, Tammy C; Lawrence, R Michael; Harikrishnan, Lalgudi S; Kamau, Muthoni G; Taylor, David S; Chen, Alice Ye A; Yin, Xiaohong; Huang, Christine S; Chang, Ming; Chen, Xue-Qing; Sleph, Paul G; Xu, Carrie; Li, Julia; Levesque, Paul; Adam, Leonard P; Wexler, Ruth R.
Afiliação
  • Finlay HJ; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Jiang J; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Rampulla R; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Salvati ME; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Qiao JX; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Wang TC; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Lawrence RM; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Harikrishnan LS; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Kamau MG; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Taylor DS; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Chen AYA; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Yin X; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Huang CS; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Chang M; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Chen XQ; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Sleph PG; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Xu C; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Li J; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Levesque P; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Adam LP; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • Wexler RR; Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
ACS Med Chem Lett ; 10(6): 911-916, 2019 Jun 13.
Article em En | MEDLINE | ID: mdl-31223447
Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N-terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide (13). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters.
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Texto completo: 1 Bases de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
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XML
PubMed Links
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Texto completo: 1 Bases de dados: MEDLINE Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos