Triazolopyridine ethers as potent, orally active mGlu2 positive allosteric modulators for treating schizophrenia

Abstract Triazolopyridine ethers with mGlu 2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)- 7m ). After oral administration at 10 mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10 mg/kg ( p.o .). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu 2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.