Abstract 11228: A Novel and Potent CETP Inhibitor, CKD-519 Exerts Strong HDL Increment and Anti-atherosclerotic Effects
Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the transfer of cholesteryl ester (CE) from HDL to apolipoprotein B (apoB)-containing lipoprotein (VLDL and LDL) in exchange for triglyceride (TG). Inhibition of the CETP is expected to reduce cardiovascular risks due to the increased level of the high-density lipoprotein-cholesterol (HDL-c).
Our discovery program identified a potent and orally available CETP inhibitor, CKD-519, which is structurally novel. CKD-519 demonstrated strong inhibitory activity against CETP in vitro (IC50=2.3 nM, human plasma). When orally administrated in 2 week studies, CKD-519 significantly elevated the HDL-c level (30~70%) in a panel of in vivo models (dyslipidemic hamster, Cynomolgus monkey and human CETP/Apo-AI transgenic mice). In a diet-induced atherosclerosis rabbit model, CKD-519 (10/30/60 mg/kg, po, 12wks) remarkably reduced lipid deposition of aortic lesions. These results strongly underline the firm development potential of CKD-519 to effectively treat the atherosclerotic cardiovascular disease.
Given the undesirable cardiovascular safety issues associated with the increased levels of aldosterone and cortisol caused by torcetrapib in human clinical studies, the effects of CKD-519 on blood pressure were measured in normal Sprague Dawley rats, a species that does not express CETP. Following the iv administration (5 mg/kg, infusion, 20 mins), in contrast to torcetrapib, CKD-519 did not alter the blood pressure or the plasma aldosterone and corticosterone levels. In addition, CKD-519 did not increase aldosterone and cortisol in a human adrenal cortical carcinoma cell line (H295R cells) without inducing aldosterone and cortisol biosynthesis enzymes (CYP 11B1 and CYP 11B2) up to 10 uM.
Based upon efficacy, PK and safety profiles, CKD-519 is currently advanced to the pre-clinical stage and expected to provide one of the leading HDL therapies for the treatments of the atherosclerotic cardiovascular diseases
- © 2013 by American Heart Association, Inc.