Further Optimization of the mGlu₁ PAM VU6024578/BI02982816: Discovery and Characterization of VU6033685

Herein, we report the further chemical optimization of the metabotropic glutamate receptor subtype 1 (mGlu₁) positive allosteric modulator (PAM) VU6024578/BI02982816 and the discovery of VU6033685/BI1752. PAM VU6033685/BI1752 was developed through an iterative process wherein, after the furanyl moiety (a potential toxicophore) was replaced by an N-linked pyrazole, a diversity screen identified a quinoline core, which was further truncated to a pyridine scaffold. PAM VU6033685/BI1752 proved to be a potent and selective mGlu₁ PAM with efficacy in both amphetamine-induced hyperlocomotion (AHL) and novel object recognition (NOR) with a clear pharmacokinetic-pharmacodynamic (PK/PD) relationship. VU6024578/BI02982816 was efficacious and well tolerated in rats but not dogs, whereas VU6033685/BI1752 elicited adverse events (AEs) in both rats and dogs. These AEs, noted in two distinct mGlu₁ PAM chemotypes, cast a shadow on an otherwise promising molecular target to address multiple symptom clusters in schizophrenic patients.