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
Departments of †Discovery Chemistry, ‡Discovery Biology, §Discovery Toxicology, ∥Preclinical Candidate Optimization, and ⊥Pharmaceutics, Bristol-Myers Squibb Company, Research and Development , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
J Med Chem. 2015 Nov 25;58(22):9010-26. doi: 10.1021/acs.jmedchem.5b01363. Epub 2015 Nov 17.
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.
胆固醇酯转运蛋白（CETP）抑制剂可提高动物和人类的高密度脂蛋白胆固醇（HDL-C）水平，并且可能通过增强逆向胆固醇转运（RCT）而具有抗动脉粥样硬化作用。在本文中，我们描述了先导化合物优化工作，该工作导致发现了一系列三苯乙胺（TPE）脲类和酰胺类化合物，它们是强效且口服可用的CETP抑制剂。化合物10g是一种强效CETP抑制剂，在人CETP/载脂蛋白B-100双转基因小鼠中，口服剂量为1mg/kg时可最大程度地抑制胆固醇酯（CE）转移活性，并且在中度高脂喂养的仓鼠中，其增加HDL胆固醇含量和大小的作用与托彻普（torcetrapib，1）相当。与化合物1存在脱靶不良反应不同，在大鼠遥测研究中未观察到10g会使血压升高，并且在H295R细胞中未检测到醛固酮合酶（CYP11B2）增加。基于其临床前特征，化合物10g进入了临床前安全性研究。
