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This work describes the discovery and characterization of novel 6-(1 H-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… Click to show full abstract
This work describes the discovery and characterization of novel 6-(1 H-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, t1/2 = 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.
Journal Title: Journal of medicinal chemistry
Year Published: 2019
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