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)

• Published in: Journal of medicinal chemistry 2015-11, Vol.58 (22), p.9010-9026
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - pharmacokinetics; Anticholesteremic Agents - pharmacology; Atherosclerosis - drug therapy; Benzamides - chemical synthesis; Benzamides - pharmacokinetics; Benzamides - pharmacology; Benzylamines - chemical synthesis; Benzylamines - pharmacokinetics; Benzylamines - pharmacology; Blood Pressure - drug effects; Cell Line; Cholesterol - metabolism; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; Cholesterol, HDL - blood; Cricetinae; Cytochrome P-450 CYP11B2 - antagonists & inhibitors; Dogs; Drug Discovery; Humans; Macaca fascicularis; Male; Mesocricetus; Mice; Mice, Transgenic; Motor Activity - drug effects; Quinolines - pharmacology; Rats; Rats, Sprague-Dawley
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01363

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.