Discovery of VU6052254: A Novel, Potent M₁ Positive Allosteric Modulator.

ABSTRACT: We recently disclosed VU0467319, a muscarinic acetylcholine receptor subtype 1 (M₁) Positive Allosteric Modulator (PAM) clinical candidate that had successfully completed a Phase I Single Ascending Dose (SAD) clinical trial, but the identification of an inactive metabolite constituting a major portion of the total plasma AUC detracted from the molecules' pharmacokinetic profile and contributed to clinical development discontinuation. Attempts to block metabolism with the incorporation of deuterium atoms proved successful in vitro and in vivo at low exposures; however, in high-dose nonclinical toxicology studies, the degree of oxidative metabolism and metabolite accumulation was comparable to that of the proteo-congener. Here, we describe a second-generation back-up

SUBMITTER: Engers JL 

PROVIDER: S-EPMC12715762 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature