Discovery, Structure–Activity Relationship, and Biological Characterization of a Novel Series of 6‑((1H‑Pyrazolo[4,3‑b]pyridin-3-yl)amino)-benzo[d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu4)

This work describes the discovery and characterization of novel 6-(1H-pyrazolo­[4,3-b]­pyridin-3-yl)­amino-benzo­[d]­isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC50 = 50.1 nM, 50.5% GluMax) and selective mGlu4 PAM with an excellent rat DMPK profile (in vivo rat CLp = 3.1 mL/min/kg, t 1/2 = 445 min, CYP1A2 IC50 > 30 μM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson’s disease.