N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators.

Abstract A novel series of N - aryl pyrrolidinonyl oxadiazoles were identified as mGluR5 positive allosteric modulators ( PAMs ). Optimization of the initial lead compound 6a led to the identification of the 12c (−) enantiomer as a potent compound with acceptable in vitro clearance, CYP, hERG and PK properties. Para substituted N - aryl pyrrolidinonyl oxadiazoles are mGluR5 PAMs while the meta and ortho substituted N - aryl pyrrolidinonyl oxadiazoles are negative allosteric modulators ( NAMs ). Para fluoro substitution on the N - aryl group and meta chloro or methyl substituents on the aryl oxadiazole moiety are optimal for mGluR5 PAM efficacy. The existence of an exquisitely sensitive ‘ PAM to NAM switch ’ within this chemotype making it challenging for simultaneous optimization of potency and drug - like properties.