title: Biphenyl-substituted oxazolidinones as cholesteryl ester transfer protein inhibitors: modifications of the oxazolidinone ring leading to the discovery of anacetrapib.
abstract: The development of the structure-activity studies leading to the discovery of anacetrapib is described. These studies focused on varying the substitution of the oxazolidinone ring of the 5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl group with the cis-stereochemistry relative to the 5-aryl group afforded compounds with increased cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing HDL-C levels in transgenic mice expressing cynomolgus monkey CETP.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, United States. cameron_smith@merck.com
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Smith
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Milton L
authors.initials: ML
authors.lastname: Hammond
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Lu
authors.forename: Joann
authors.initials: J
authors.lastname: Napolitano
authors.forename: Gayle E
authors.initials: GE
authors.lastname: Taylor
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Thompson
authors.forename: Matt S
authors.initials: MS
authors.lastname: Anderson
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Suzanne S
authors.initials: SS
authors.lastname: Eveland
authors.forename: Qiu
authors.initials: Q
authors.lastname: Guo
authors.forename: Sheryl A
authors.initials: SA
authors.lastname: Hyland
authors.forename: Denise P
authors.initials: DP
authors.lastname: Milot
authors.forename: Carl P
authors.initials: CP
authors.lastname: Sparrow
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cumiskey
authors.forename: Melanie
authors.initials: M
authors.lastname: Latham
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Peterson
authors.forename: Ray
authors.initials: R
authors.lastname: Rosa
authors.forename: James V
authors.initials: JV
authors.lastname: Pivnichny
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Suoyu S
authors.initials: SS
authors.lastname: Xu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sinclair
mesh_terms: D000818:Animals; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008076:Cholesterol, HDL / Q000097:blood; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D023303:Oxazolidinones; D011994:Recombinant Proteins; C530884:anacetrapib