120th General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Exhibition Hall 2+3
Time 10월 19일 (목요일) 11:00~12:30
Code MEDI.P-321
Subject Discovery of Cholesteryl Ester Transfer Protein Inhibitor for the Treatment of Dyslipidemia/Cardiovascular Diseases
Authors Ga young Park*, Minsoo Song*
Daegu Gyeongbuk Medical Innovation Foundation, Korea
Abstract Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein which catalyzes a mutual exchange of cholestery esters (CEs) and triglycerides (TGs) among lipoproteins such as high density lipoprotein (HDL), low density lipoprotein (LDL), and very low density lipoprotein (VLDL). Physiological role of CETP is to transfer CEs from HDL to LDL/VLDL in exchange for TGs, consequently decreasing HDL-C levels and increasing LDL-C levels in plasma. Such event by CETP in plasma might be proatherogenic based upon epidemiological studies and therefore, inhibition of CETP could be a potential therapy to reduce atherosclerotic cardiovascular disease (ASCVD) risk. Accordingly, CETP has been targeted intensively in drug-development society especially by major pharmaceutical companies, and the most advanced study is about anacetrapib from Merck in clinical phase III, waiting for the final results. Recently, we designed a novel series of small molecules as CETP inhibitor for ASCVD and over 130 compounds were synthesized. In vitro CETP inhibitory activity of each compound was obtained by single dose (80nM) treatment of inhibitor using commercially available assay kit. Several compounds were highly potent and tested for ADME/T assay and rodent PK experiments. Our lead compound showed comparable efficacy to anacetrapib both in vitro and in vivo. Efficacy dose of the lead compound was determined based on mouse PK data and subjected to in vivo efficacy experiment using hCETP/ApoB dual transgenic mice. One month-period of efficacy test with 4 animal groups (vehicle, anacetrapib 10 mpk QD, DN201929 10 mpk QD, and DN201929 30 mpk QD) was executed. Analysis of the efficacy data of HDL/LDL levels and histopathologic examination provided promising results. Detailed experimental and efficacy data are presented in this poster.
E-mail pgy2220@dgmif.re.kr