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)

被引：10

作者：

Qiao, Jennifer X. ^{[1
]}

Wang, Tammy C. ^{[1
]}

Adam, Leonard P. ^{[2
]}

Chen, Alice Ye A. ^{[2
]}

Taylor, David S. ^{[2
]}

Yang, Richard Z. ^{[2
]}

Zhuang, Shaobin ^{[2
]}

Sleph, Paul G. ^{[2
]}

Li, Julia P. ^{[3
]}

Li, Danshi ^{[3
]}

Yin, Xiaohong ^{[2
]}

Chang, Ming ^{[4
]}

Chen, Xue-Qing ^{[5
]}

Shen, Hong ^{[4
]}

Li, Jianqing ^{[1
]}

Smith, Daniel ^{[1
]}

Wu, Dauh-Rurng ^{[1
]}

Leith, Leslie ^{[1
]}

Harikrishnan, Lalgudi S. ^{[1
]}

Kamau, Muthoni G. ^{[1
]}

Miller, Michael M. ^{[1
]}

Bilder, Donna ^{[1
]}

Rampulla, Richard ^{[1
]}

Li, Yi-Xin ^{[4
]}

Xu, Carrie ^{[4
]}

Lawrence, R. Michael ^{[1
]}

Poss, Michael A. ^{[1
]}

Levesque, Paul ^{[3
]}

Gordon, David A. ^{[2
]}

Huang, Christine S. ^{[4
]}

Finlay, Heather J. ^{[1
]}

Wexler, Ruth R. ^{[1
]}

Salvati, Mark E. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Dept Discovery Chem, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Co, Dept Discovery Biol, Princeton, NJ 08543 USA

[3] Bristol Myers Squibb Co, Dept Discovery Toxicol, Princeton, NJ 08543 USA

[4] Bristol Myers Squibb Co, Dept Preclin Candidate Optimizat, Princeton, NJ 08543 USA

[5] Bristol Myers Squibb Co, Dept Pharmaceut, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 22期

关键词：

CORONARY-HEART-DISEASE; HIGH-DENSITY-LIPOPROTEIN; ASYMMETRIC-SYNTHESIS; CETP INHIBITORS; ARTERY-DISEASE; BLOOD-PRESSURE; VINYL ETHERS; RAISING HDL; HIGH-RISK; TORCETRAPIB;

D O I：

10.1021/acs.jmedchem.5b01363

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：9010 / 9026

页数：17

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