123rd General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Exhibition Hall 2
Time 4월 18일 (목요일) 11:00~12:30
Code MEDI.P-422
Subject Development and Lead optimization of CETP inhibitors for cardiovascular diseases
Authors Eunhye Lee, Soong-Hyun Kim, Ga Young Park, Eun Bi Ko, Chunyoung Im, Minsoo Song*
New Drug Development Center (NDDC), Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 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 has been on anacetrapib from Merck with successful efficacy in clinical trial phase III. Recently, we designed a novel series of small molecules as CETP inhibitor for ASCVD and over 150 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 (anacetrapib vs DN201929) 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 leh430@dgmif.re.kr