molecules of the month

“compound 2”

potent, oral heme-displacing IDO1 inhibitor

low predicted human dose (<10 mg QD)

from ALIS mass-based binding screen + SBDD

ACS Med. Chem. Lett., Jul. 15, 2020

Merck & Co., Boston, MA

Structure of compound 2
1 min read

“compound 2” is a heme-displacing IDO1 inhibitor with a similar binding mode to BMS-986205 with a low projected human dose. A bis-amide hit was generated from a mass-spectrometry based binding screen, and optimized through structure-based drug design. An initial benzamide lead was metabolically unstable due to rapid amide hydrolysis, but this was addressed by replacing a central phenyl ring with the bicyclo[1.1.1]propane (BCP) motif. While the BCP has been touted as a phenyl isostere, it is rare to see central phenyl groups replaced without significant losses in activity. Impressively, the BCP replacement led to a substantially improved series of molecules for the Merck team, convincing me to try this move more often!

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