title: 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).
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.
authors.affiliation: 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.
authors.forename: Jennifer X
authors.initials: JX
authors.lastname: Qiao
authors.affiliation: 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.
authors.forename: Tammy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Leonard P
authors.initials: LP
authors.lastname: Adam
authors.affiliation: 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.
authors.forename: Alice Ye A
authors.initials: AY
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: David S
authors.initials: DS
authors.lastname: Taylor
authors.affiliation: 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.
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Shaobin
authors.initials: S
authors.lastname: Zhuang
authors.affiliation: 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.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Sleph
authors.affiliation: 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.
authors.forename: Julia P
authors.initials: JP
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Danshi
authors.initials: D
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yin
authors.affiliation: 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.
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Xue-Qing
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Dauh-Rurng
authors.initials: DR
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Leslie
authors.initials: L
authors.lastname: Leith
authors.affiliation: 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.
authors.forename: Lalgudi S
authors.initials: LS
authors.lastname: Harikrishnan
authors.affiliation: 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.
authors.forename: Muthoni G
authors.initials: MG
authors.lastname: Kamau
authors.affiliation: 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.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Miller
authors.affiliation: 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.
authors.forename: Donna
authors.initials: D
authors.lastname: Bilder
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Rampulla
authors.affiliation: 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.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Carrie
authors.initials: C
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: R Michael
authors.initials: RM
authors.lastname: Lawrence
authors.affiliation: 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Poss
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Levesque
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Gordon
authors.affiliation: 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.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Finlay
authors.affiliation: 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.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: 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.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Salvati
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001596:Benzylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000097:blood; D006224:Cricetinae; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000924:Anticholesteremic Agents; C000605770:BMS-795311; D001549:Benzamides; D001596:Benzylamines; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D011804:Quinolines; C483909:torcetrapib; D002784:Cholesterol; D019405:Cytochrome P-450 CYP11B2