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.

Design and synthesis of potent inhibitors of cholesteryl ester transfer protein (CETP) exploiting a 1,2,3,4-tetrahydroquinoline platform.

Tetrahydroquinoline A is a potent inhibitor of the cholesterol ester transfer protein (CETP), a target for the treatment of low HDL-C and atherosclerosis. Low HDL-C has been identified as a key risk factor for cardiovascular disease in addition to high LDL-C, the target of the statin drugs. Tetrahydroquinoline A inhibits partially purified CETP with an IC(50) of 39nM.

Dihydro-[1H]-quinolin-2-ones as retinoid X receptor (RXR) agonists for potential treatment of dyslipidemia.

A number of RXR modulators with novel structural features were synthesized and screened in the functional assays. The synthesis and the structure-activity relationship within the series of compounds will be presented. Some in vivo data generated in the models for dyslipidemia and diabetes will also be presented.

RXR-LXR heterodimer modulators for the potential treatment of dyslipidemia.

A number of RXR agonists were synthesized and screened in functional assays. The synthesis and the structure-activity relationship (SAR) within the series of compounds will be presented. Some in vivo data in rodent models for dyslipidemia and diabetes will also be presented.

Nuclear receptors as potential targets for modulating reverse cholesterol transport.

This review describes the role of nuclear receptors in the regulation of genes involved in cholesterol transport and synthetic modulators of these receptors. Increasing the efflux of cholesterol from peripheral cells, such as lipid-laden macrophages, through a process called reverse cholesterol transport (RCT) requires HDL. Increasing the circulating levels of HDL, as well as the efficiency of the RCT process, could result in a reduction in the development of coronary artery disease and atherosclerosis.