2. Academic Validation
  3. Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties

Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties

  • J Med Chem. 2021 Sep 23;64(18):13215-13258. doi: 10.1021/acs.jmedchem.1c00959.
Petr Vachal 1,  Joseph L Duffy 1,  Louis-Charles Campeau 1,  Rupesh P Amin 1,  Kaushik Mitra 1,  Beth Ann Murphy 1,  Pengcheng P Shao 1,  Peter J Sinclair 1,  Feng Ye 1,  Revathi Katipally 1,  Zhijian Lu 1,  Debra Ondeyka 1,  Yi-Heng Chen 1,  Kake Zhao 1,  Wanying Sun 1,  Sriram Tyagarajan 1,  Jianming Bao 1,  Sheng-Ping Wang 1,  Josee Cote 1,  Concetta Lipardi 1,  Daniel Metzger 1,  Dennis Leung 1,  Georgy Hartmann 1,  Gordon K Wollenberg 1,  Jian Liu 1,  Lushi Tan 1,  Yingju Xu 1,  Qinghao Chen 1,  Guiquan Liu 2,  Robert O Blaustein 1,  Douglas G Johns 1
Affiliations

Affiliations

  • 1 Merck & Co., Inc., 2000 Galloping Hill Rd., Kenilworth, New Jersey 07033, United States.
  • 2 WuXi AppTec, 90 Delin Rd., Waigaoqiao Free Trade Zone, Shanghai 200131, China.
PMID: 34375108 DOI: 10.1021/acs.jmedchem.1c00959
Abstract

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP Inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP Inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

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