Inhibitors of cholesteryl ester transfer protein (CETP) elevate HDL levels human clinical trials. However, the first CETP inhibitors proved toxic in pivotal trials or showed minimal therapeutic benefit. Anacetrapib showed some clinical benefit but is high lipophilic. This Viewpoint highlights efforts to optimize anacetrapib to a best-in-class CETP inhibitor.

23 Sep 2021·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Duffy, Joseph L. ; Katipally, Revathi ; Zhao, Kake ; Wang, Sheng-Ping ; Liu, Guiquan ; Cote, Josee ; Tyagarajan, Sriram ; Liu, Jian ; Xu, Yingju ; Ye, Feng ; Shao, Pengcheng P. ; Wollenberg, Gordon K. ; Campeau, Louis-Charles ; Ondeyka, Debra ; Bao, Jianming ; Amin, Rupesh P. ; Vachal, Petr ; Metzger, Daniel ; Hartmann, Georgy ; Leung, Dennis ; Murphy, Beth Ann ; Johns, Douglas G. ; Chen, Qinghao ; Sun, Wanying ; Lipardi, Concetta ; Mitra, Kaushik ; Tan, Lushi ; Lu, Zhijian ; Sinclair, Peter J. ; Blaustein, Robert O. ; Chen, Yi-Heng

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.

Journal of Medicinal Chemistry

An Analysis of Successful Hit-to-Clinical Candidate Pairs

Author: Brown, Dean G.

An anal. of 156 published/clin. candidates from the Journal of Medicinal Chem. between 2018 and 2021 was conducted to identify lead generation strategies most frequently employed leading to drug candidates.As in a previous publication, the most frequent lead generation strategies resulting in clin. candidates were from known compounds (59%) followed by random screening approaches (21%).The remainder of the approaches included directed screening, fragment screening, DNA-encoded library screening (DEL), and virtual screening.An anal. of similarity was also conducted based on Tanimoto-MCS and revealed most clin. candidates were distant from their original hits; however, most shared a key pharmacophore that translated from hit-to-clin. candidate.An examination of frequency of oxygen, nitrogen, fluorine, chlorine, and sulfur incorporation in clin. candidates was also conducted.The three most similar and least similar hit-to-clin. pairs from random screening were examined to provide perspective on changes that occur that lead to successful clin. candidates.

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Indication	Highest Phase	Country/Location	Organization	Date
Coronary Artery Disease	Preclinical	United States	Merck & Co., Inc.	10 Aug 2021

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