Abstract 11806: Ds-1442b is a Novel, Potent Cetp Inhibitor That Reduces Atherosclerosis by Hdl Elevation and Non-hdl Reduction
Elevated LDL-cholesterol and reduced HDL-cholesterol are major risk factors for the development of cardiovascular disease. Inhibition of CETP is considered as a therapy to increase HDL and lower LDL levels, suggesting that CETP inhibition is antiatherogenic. Here we report the discovery of a novel potent CETP inhibitor, DS-1442b, which has good oral bioavailability even in suspension formulation. To evaluate the effect of DS-1442b on the plasma lipid levels, DS-1442b was administered orally for 7 days to human CETP/Apo B transgenic mice in which the lipoprotein distribution resembles a human profile. Treatment with DS-1442b at ≥0.1 mg/kg inhibited plasma CETP activity in a dose-dependent manner and at ≥1 mg/kg or more almost completely abolished. In concordance with the ex vivo CETP inhibition, DS-1442b significantly elevated HDL-cholesterol (>85%) with increases of all the HDL subfractions (very small HDL to very large HDL, 8 - 16 nm) analyzed by a gel filtration-high performance liquid chromatography. In addition, DS-1442b significantly lowered LDL- (>40%) and VLDL-cholesterol (>50%). Next, we investigated the effect of DS-1442 on progression of atherosclerosis in a Western diet-fed LDLR-/- mice expressing human CETP, in which there was no difference in plasma total cholesterol levels, however HDL/LDL ration significantly decreased compared with LDLR-/- mice with no CETP activity (P<0.01). At 8 weeks, LDLR-/-CETP+/- mice exhibited significantly advanced atherosclerotic lesions in the aortic root compared with LDLR-/- mice (299000 vs. 17600 µm2, P<0.01). As observed in human CETP/Apo B transgenic mice, DS-1442b elevated HDL-cholesterol at ≥0.1 mg/kg (P<0.05) and decreased LDL-cholesterol at ≥0.3 mg/kg (P<0.05) and VLDL-cholesterol at ≥1 mg/kg (P<0.05). Treatment with DS-1442b at 0.1 mg/kg or more reduced the atherosclerotic lesion area by similar extent to that in LDLR-/- mice (P<0.05). The data clearly indicate that the reduced lesion area by CETP inhibition is associated with increased levels of HDL-cholesterol and optimally with concomitant decreased non-HDL-cholesterol levels. The present work suggests that DS-1442b may be suitable to be further evaluated in human clinical trials.
- © 2012 by American Heart Association, Inc.