molecules of the month

compound 25

kinome selective, CNS-penetrant, type I LRRK2 inhibitor

in vivo activity in preclinical PK/PD model

scaffold hopping + opt. of MLi-2

J. Med. Chem., December 7, 2022

Merck & Co., Boston, MA & Kenilworth, NJ

compound 25 chemical structure kinome selective, CNS-penetrant, type I LRRK2 inhibitor - Merck & Co., Boston, MA & Kenilworth, NJ
4 mins read

What is it? “Compound 25” is a selective, CNS-penetrant, ATP-competitive LRRK2 inhibitor that entered preclinical candidate enabling studies but was discontinued for undisclosed reasons. The molecule possesses two interesting chemical features: a “bow-tie” spirocyclopropyl group that made a significant impact on potency and overall properties, and a non-classical C-H hinge binder. The molecule was nominated by reviewer Dennis Koester, who says: “Although they terminated the compound for undisclosed but scientific reasons, I think it is a wonderful drug discovery story. Of note for a CNS target, they only looked at BCRP late in the program and discovered the compound to be a BCRP substrate and inhibitor leading to a low Kpu,u in NHPs compared to rats. The compound was not…

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