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

Aihua Wang; Catherine P Prouty; Patricia D Pelton; Maria Yong; Keith T Demarest; William V Murray; Gee-Hong Kuo

doi:10.1016/j.bmcl.2009.12.096

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

Bioorg Med Chem Lett. 2010 Feb 15;20(4):1432-5. doi: 10.1016/j.bmcl.2009.12.096. Epub 2010 Jan 4.

Authors

Aihua Wang¹, Catherine P Prouty, Patricia D Pelton, Maria Yong, Keith T Demarest, William V Murray, Gee-Hong Kuo

Affiliation

¹ Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh & McKean Roads, PO Box 776, Spring House, PA 19477-0776, USA. [email protected]

PMID: 20089400
DOI: 10.1016/j.bmcl.2009.12.096

Abstract

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.

MeSH terms

Administration, Oral
Animals
Benzoxazines / chemical synthesis*
Benzoxazines / chemistry
Benzoxazines / pharmacology
Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
Cholesterol Ester Transfer Proteins / genetics
Cricetinae
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Female
Humans
Inhibitory Concentration 50
Male
Mice
Mice, Transgenic
Molecular Structure
Rats

Substances

Benzoxazines
Cholesterol Ester Transfer Proteins
Enzyme Inhibitors