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
  • 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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