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

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 (IC50 = 26 nM) possessed a favorable pharmacokinetic profile with good oral bioavailability in rat (F = 53%) and long human liver microsome stability (t1/2 = 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.

2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazine 6a is a potent inhibitor (IC50 = 26 nM) of cholesteryl ester transfer protein (CETP). It possesses a favorable pharmacokinetic profile and long human liver microsome stability (t1/2 = 62 min). It increases HDL-C in animal model studies. The SAR of this series is discussed herein.Figure optionsDownload as PowerPoint slide