molecules of the month


potential best-in-class CETP inh. (<1 mg QD)

completed Ph. I in HV; discont. as backup

from anacetrapib

Journal of Medicinal Chemistry

Merck & Co., Kenilworth, NJ, USA

1 min read

The Merck CETP inhibitor backup, MK-8262, is potential best-in-class CETP inhibitor, which was only discontinued as a backup due to the success of its predecessor, anacetrapib in Ph. III. Reviewer Kim Huard thought this CETP inhibitor was a great piece of work from Merck, and is a great example how to deal with a very lipophilic binding site, optimizing total rather than unbound exposure and using TPSA as a surrogate for lipophilicity since the molecules were outside the reliably measurable range for LogD. “I also liked their strategy of adding a carboxylic acid to reduce lipophilicity while shifting non-specific binding from tissue towards plasma proteins,” which likely contributes to the long half-life observed. MK-8262 completed a Ph. I study in healthy volunteers and…

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