7BPI

The crystal structue of PDE10A complexed with 14

7BPI の概要

• エントリーDOI: 10.2210/pdb7bpi/pdb
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: pde10a inhibitor, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75276.95

構造登録者

Yang, Y.,Zhang, S.,Zhou, Q.,Huang, Y.-Y.,Guo, L.,Luo, H.-B. (登録日: 2020-03-22, 公開日: 2021-01-27, 最終更新日: 2023-11-29)

主引用文献

Yang, Y.,Zhang, S.,Zhou, Q.,Zhang, C.,Gao, Y.,Wang, H.,Li, Z.,Wu, D.,Wu, Y.,Huang, Y.Y.,Guo, L.,Luo, H.B.
Discovery of highly selective and orally available benzimidazole-based phosphodiesterase 10 inhibitors with improved solubility and pharmacokinetic properties for treatment of pulmonary arterial hypertension.
Acta Pharm Sin B, 10:2339-2347, 2020

PubMed Abstract: Optimization efforts were devoted to discover novel PDE10A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension (PAH) starting from the previously synthesized inhibitor . As a result, a potent and highly selective PDE10A inhibitor, 3HCl (half maximal inhibitory concentration, IC = 2.8 nmol/L and 3500-fold selectivity) exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of 50% was identified with the aid of efficient methods of binding free energy predictions. Animal PAH studies showed that the improvement offered by 3HCl [2.5 mg/kg, oral administration (.)] was comparable to tadalafil (5.0 mg/kg, .), verifying the feasibility of PDE10A inhibitors for the anti-PAH treatment. The crystal structure of the PDE10A- complex illustrates their binding pattern, which provided a guideline for rational design of highly selective PDE10A inhibitors.

PubMed: 33354505
DOI: 10.1016/j.apsb.2020.04.003

実験手法

X-RAY DIFFRACTION (2.40008632403 Å)