Biphenyl-Substituted Oxazolidinones as Cholesteryl Ester Transfer Protein Inhibitors: Modifications of the Oxazolidinone Ring Leading to the Discovery of Anacetrapib

• Published in: Journal of medicinal chemistry Vol. 54; no. 13; pp. 4880 - 4895
• Main Authors: Smith, Cameron J, Ali, Amjad, Hammond, Milton L, Li, Hong, Lu, Zhijian, Napolitano, Joann, Taylor, Gayle E, Thompson, Christopher F, Anderson, Matt S, Chen, Ying, Eveland, Suzanne S, Guo, Qiu, Hyland, Sheryl A, Milot, Denise P, Sparrow, Carl P, Wright, Samuel D, Cumiskey, Anne-Marie, Latham, Melanie, Peterson, Laurence B, Rosa, Ray, Pivnichny, James V, Tong, Xinchun, Xu, Suoyu S, Sinclair, Peter J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.07.2011; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; Cholesterol Ester Transfer Proteins - chemistry; Cholesterol, HDL - blood; Humans; Life Sciences & Biomedicine; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxazolidinones - chemical synthesis; Oxazolidinones - pharmacokinetics; Oxazolidinones - pharmacology; Pharmacology & Pharmacy; Recombinant Proteins - chemistry; Science & Technology; Stereoisomerism; Structure-Activity Relationship; HEALTHY-SUBJECTS; HIGH-RISK; THERAPEUTIC TARGET; DOUBLE-BLIND; HDL CHOLESTEROL; CETP INHIBITOR; CORONARY-HEART-DISEASE; 14 RANDOMIZED-TRIALS; BLOOD-PRESSURE; HIGH-DENSITY-LIPOPROTEIN
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm200484c

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.