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]

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• 作者：Jennifer X. Qiao ; Tammy C. Wang ; Leonard P. Adam ; Alice Ye A. Chen ; David S. Taylor ; Richard Z. Yang ; Shaobin Zhuang ; Paul G. Sleph ; Julia P. Li ; Danshi Li ; Xiaohong Yin ; Ming Chang ; Xue-Qing Chen ; Hong Shen ; Jianqing Li ; Daniel Smith ; Dauh-Rurng Wu ; Leslie Leith ; Lalgudi S. Harikrishnan ; Muthoni G. Kamau ; Michael M. Miller ; Donna Bilder ; Richard Rampulla ; Yi-Xin Li ; Carrie Xu ; R. Michael Lawrence ; Michael A. Poss ; Paul Levesque ; David A. Gordon ; Christine S. Huang ; Heather J. Finlay ; Ruth R. Wexler ; Mark E. Salvati
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 25, 2015
• 年：2015
• 卷：58
• 期：22
• 页码：9010-9026
• 全文大小：779K
• ISSN：1520-4804

文摘

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.