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Discovery of Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A). 2014
Essa Hu, and
Kristin Andrews, and
Samer Chmait, and
Xiaoning Zhao, and
Carl Davis, and
Silke Miller, and
Geraldine Hill Della Puppa, and
Mary Dovlatyan, and
Hang Chen, and
Dianna Lester-Zeiner, and
Jessica Able, and
Christopher Biorn, and
Ji Ma, and
Jianxia Shi, and
James Treanor, and
Jennifer R Allen
Department of Medicinal Chemistry, Department of Molecular Structure, Department of Pharmacokinetics and Drug Metabolism, and Department of Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
We report the discovery of novel imidazo[4,5-b]pyridines as potent and selective inhibitors of PDE10A. The investigation began with our recently disclosed ketobenzimidazole 1, which exhibited single digit nanomolar PDE10A activity but poor oral bioavailability. To improve oral bioavailability, we turned to novel scaffold imidazo[4,5-b]pyridine 2, 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 7 and 24 in human PDE10A helped to elucidate the key bonding interactions. Five of the most potent and structurally diverse imidazo[4,5-b]pyridines (4, 7, 12b, 24a, and 24b) with PDE10A IC50 values ranging from 0.8 to 6.7 nM were advanced into receptor occupancy studies. Four of them (4, 12b, 24a, and 24b) achieved 55-74% RO at 10 mg/kg po.
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