Abstract 11879: A Novel and Potent CETP Inhibitor K-312 with PCSK9 Inhibitory Property, Exerts Strong Reduction of LDL-C and Anti-atherosclerotic Effects

Abstract

[Introduction] CETP (cholesterol ester transfer protein) mediates the transfer and exchange of cholesteryl ester and triglyceride between plasma lipoproteins. Several CETP inhibitors are now under clinical trials and expected to suppress cardiovascular events. We developed a novel CETP inhibitor K-312 with PCSK9 inhibitory potency.

[Objective] We investigated the potency of K-312 on CETP inhibition, improvements of lipid profiles in hamsters, and anti-atherosclerotic effects in cholesterol-fed rabbits.

[Methods and Results] K-312 showed strong CETP inhibition in human plasma (IC₅₀= 0.06 μM) and hamster plasma (IC₅₀= 0.10 μM) compared with anacetrapib (IC₅₀= 0.20 μM) or evacetrapib (IC₅₀= 0.18 μM) in human plasma. In hamsters, single administration of K-312 showed persistent CETP inhibition after 24 h (n=3). In hamsters, 2-week administration of K-312 (3 mg/kg) lowered LDL-C and triglyceride by 20% and 26%, respectively, and increased HDL-C by 78% (n=6-9). In cholesterol-fed rabbits, K-312 (10 mg/kg) as well as anacetrapib (30 mg/kg) increased HDL-C levels dramatically during 18 weeks of administration, although only K-312 could reduce non-HDL-C levels through experimental period. To confirm the ability of increased HDL-C to remove cholesterol, in vitro cholesterol efflux was analyzed. Cholesterol efflux from macrophages to serum treated with K-312 or anacetrapib was increased equivalently (n=12). Additionally, en face analysis of aortic lesion revealed that K-312 decreased lipid deposition by 54% (n=14-15). To investigate the mechanisms of LDL-C reduction by K-312, we focused PCSK9 (proprotein convertase subtilisin/kexin 9), which degrades LDL receptor. PCSK9 production in HepG2 cells was significantly decreased by K-312 (1 μM), but not by anacetrapib (3 μM) (n=4). Enhancement of PCSK9 production by pitavastatin was also suppressed by K-312.

[Conclusion] These results suggest that K-312 exerts strong reduction in LDL-C levels, and anti-atherosclerotic effects, presumably due to both its potent CETP inhibitory action and suppressing property of PCSK9 production.