4P0N

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

4P0N の概要

• エントリーDOI: 10.2210/pdb4p0n/pdb
• 分子名称: 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)
• 機能のキーワード: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q9Y233
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 80207.07

構造登録者

Chmait, S. (登録日: 2014-02-21, 公開日: 2014-10-01, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.08 Å)