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 (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.
Wang
Aihua
A
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh & McKean Roads, PO Box 776, Spring House, PA 19477-0776, USA. awang1@its.jnj.com
Prouty
Catherine P
CP
Pelton
Patricia D
PD
Yong
Maria
M
Demarest
Keith T
KT
Murray
William V
WV
Kuo
Gee-Hong
GH
D000284:Administration, Oral; D000818:Animals; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006224:Cricetinae; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D051381:Rats
D048588:Benzoxazines; D053480:Cholesterol Ester Transfer Proteins; D004791:Enzyme Inhibitors