4MVH

Crystal Structure of PDE10A with Novel Keto-Benzimidazole Inhibitor

4MVH の概要

• エントリーDOI: 10.2210/pdb4mvh/pdb
• 関連するPDBエントリー: 4MUW
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: pde10a, phosphodiesterase 10a, inhibitors, keto-benzimidazoles, 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: 83368.02

構造登録者

Chmait, S.,Jordan, S. (登録日: 2013-09-24, 公開日: 2013-10-23, 最終更新日: 2024-11-27)

主引用文献

Hu, E.,Kunz, R.K.,Chen, N.,Rumfelt, S.,Siegmund, A.,Andrews, K.,Chmait, S.,Zhao, S.,Davis, C.,Chen, H.,Lester-Zeiner, D.,Ma, J.,Biorn, C.,Shi, J.,Porter, A.,Treanor, J.,Allen, J.R.
Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A).
J.Med.Chem., 56:8781-8792, 2013

PubMed Abstract: Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.

PubMed: 24102193
DOI: 10.1021/jm401234w

実験手法

X-RAY DIFFRACTION (2.496 Å)