Synthesis and discovery of 2,3-dihydro-3,8-diphenylbenzo[1,4]oxazines as a novel class of potent cholesteryl ester transfer protein inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (4), p.1432-1435
• Main Authors: Wang, Aihua, Prouty, Catherine P., Pelton, Patricia D., Yong, Maria, Demarest, Keith T., Murray, William V., Kuo, Gee-Hong
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Atherosclerosis; Benzoxazines - chemical synthesis; Benzoxazines - chemistry; Benzoxazines - pharmacology; CETP; CETP inhibitors; Cholesterol Ester Transfer Proteins - antagonists & inhibitors; Cholesterol Ester Transfer Proteins - genetics; Cholesteryl ester transfer protein; Cricetinae; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Female; HDL-C; Humans; Inhibitory Concentration 50; Male; Mice; Mice, Transgenic; Molecular Structure; Rats
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.12.096

2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazine 6a is a potent inhibitor (IC 50 = 26 nM) of cholesteryl ester transfer protein (CETP). It possesses a favorable pharmacokinetic profile and long human liver microsome stability ( t 1/2 = 62 min). It increases HDL-C in animal model studies. The SAR of this series is discussed herein. 2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazines were identified as a new class of potent cholesteryl ester transfer protein inhibitors. The most potent compound 6a (IC 50 = 26 nM) possessed a favorable pharmacokinetic profile with good oral bioavailability in rat ( F = 53%) and long human liver microsome stability ( t 1/2 = 62 min). It increased HDL-C in human CETP transgenic mice and high-fat fed hamsters. The structure and activity relationship of this series will be described in this Letter.