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).
J Med Chem
; 58(22): 9010-26, 2015 Nov 25.
Article
em 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzamidas
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Benzilaminas
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Proteínas de Transferência de Ésteres de Colesterol
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Anticolesterolemiantes
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2015
Tipo de documento:
Article