molecules of the month

The BMS factor XIa inhibitor, milvexian (BMS-986177), is an oral antithrombotic with a Ki of 0.11 nM. A member of this macrocyclic series was previously highlighted as one of 2020’s Molecules of the Year. Poor pharmaceutic properties from previous preclinical molecules such as solubility were addressed resulting in this candidate. Milvexian is a Ph. II clinical candidate for the prevention and treatment of thromboembolic disorders (secondary stroke prevention (NCT03766581) and venous thromboembolism prevention in total knee replacement surgery (NCT03891524), completed Ph. I study = NCT02608970). Interesting points from the paper include the introduction of two polar heterocycles from the starting point while improving properties and maintaining potency, and replacement of a pyrazole N-methyl group with a difluoromethyl group to improve metabolic stability. This molecular “rule-breaker”…