1432055-45-2Relevant articles and documents
Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties ()
Vachal, Petr,Duffy, Joseph L.,Campeau, Louis-Charles,Amin, Rupesh P.,Mitra, Kaushik,Murphy, Beth Ann,Shao, Pengcheng P.,Sinclair, Peter J.,Ye, Feng,Katipally, Revathi,Lu, Zhijian,Ondeyka, Debra,Chen, Yi-Heng,Zhao, Kake,Sun, Wanying,Tyagarajan, Sriram,Bao, Jianming,Wang, Sheng-Ping,Cote, Josee,Lipardi, Concetta,Metzger, Daniel,Leung, Dennis,Hartmann, Georgy,Wollenberg, Gordon K.,Liu, Jian,Tan, Lushi,Xu, Yingju,Chen, Qinghao,Liu, Guiquan,Blaustein, Robert O.,Johns, Douglas G.
supporting information, p. 13215 - 13258 (2021/09/02)
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.
