4P0N

Crystal structure of PDE10a with a novel Imidazo[4,5-b]pyridine inhibitor

Summary for 4P0N

• Entry DOI: 10.2210/pdb4p0n/pdb
• Descriptor: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, N-[trans-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl]-1,3-benzothiazol-2-amine, N-[cis-3-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl]-1,3-benzothiazol-2-amine, ... (7 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q9Y233
• Total number of polymer chains: 2
• Total formula weight: 80207.07

Authors

Chmait, S. (deposition date: 2014-02-21, release date: 2014-10-01, Last modification date: 2024-10-23)

Primary citation

Hu, E.,Andrews, K.,Chmait, S.,Zhao, X.,Davis, C.,Miller, S.,Hill Della Puppa, G.,Dovlatyan, M.,Chen, H.,Lester-Zeiner, D.,Able, J.,Biorn, C.,Ma, J.,Shi, J.,Treanor, J.,Allen, J.R.
Discovery of Novel Imidazo[4,5-b]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A).
Acs Med.Chem.Lett., 5:700-705, 2014

PubMed Abstract: 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.

PubMed: 24944747
DOI: 10.1021/ml5000993

Experimental method

X-RAY DIFFRACTION (2.08 Å)