Discovery of VU0467485/AZ13713945: An M₄ PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia

Abstract

Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M₄) positive allosteric modulators (PAMs). Compound <b>6c</b> (VU0467485) possesses robust <i>in vitro</i> M₄ PAM potency across species and <i>in vivo</i> efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, <b>6c</b> (VU0467485) was evaluated as a preclinical development candidate.