Discovery of Novel Imidazo[4,5‑<i>b</i>]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)

We report the discovery of novel imidazo­[4,5-<i>b</i>]­pyridines as potent and selective inhibitors of PDE10A. The investigation began with our recently disclosed ketobenzimidazole <b>1</b>, which exhibited single digit nanomolar PDE10A activity but poor oral bioavailability. To improve oral bioavailability, we turned to novel scaffold imidazo­[4,5-<i>b</i>]­pyridine <b>2</b>, which not only retained nanomolar PDE10A activity but was also devoid of the morpholine metabolic liability. Structure–activity relationship studies were conducted systematically to examine how various regions of the molecule impacted potency. X-ray cocrystal structures of compounds <b>7</b> and <b>24</b> in human PDE10A helped to elucidate the key bonding interactions. Five of the most potent and structurally diverse imidazo­[4,5-<i>b</i>]­pyridines (<b>4</b>, <b>7</b>, <b>12b</b>, <b>24a</b>, and <b>24b</b>) with PDE10A IC₅₀ values ranging from 0.8 to 6.7 nM were advanced into receptor occupancy studies. Four of them (<b>4</b>, <b>12b</b>, <b>24a</b>, and <b>24b</b>) achieved 55–74% RO at 10 mg/kg po

Discovery of Novel Imidazo[4,5‑<i>b</i>]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)

We report the discovery of novel imidazo­[4,5-<i>b</i>]­pyridines as potent and selective inhibitors of PDE10A. The investigation began with our recently disclosed ketobenzimidazole <b>1</b>, which exhibited single digit nanomolar PDE10A activity but poor oral bioavailability. To improve oral bioavailability, we turned to novel scaffold imidazo­[4,5-<i>b</i>]­pyridine <b>2</b>, which not only retained nanomolar PDE10A activity but was also devoid of the morpholine metabolic liability. Structure–activity relationship studies were conducted systematically to examine how various regions of the molecule impacted potency. X-ray cocrystal structures of compounds <b>7</b> and <b>24</b> in human PDE10A helped to elucidate the key bonding interactions. Five of the most potent and structurally diverse imidazo­[4,5-<i>b</i>]­pyridines (<b>4</b>, <b>7</b>, <b>12b</b>, <b>24a</b>, and <b>24b</b>) with PDE10A IC₅₀ values ranging from 0.8 to 6.7 nM were advanced into receptor occupancy studies. Four of them (<b>4</b>, <b>12b</b>, <b>24a</b>, and <b>24b</b>) achieved 55–74% RO at 10 mg/kg po