6IWI

Crystal structure of PDE5A in complex with a novel inhibitor

6IWI の概要

• エントリーDOI: 10.2210/pdb6iwi/pdb
• 分子名称: cGMP-specific 3',5'-cyclic phosphodiesterase, MAGNESIUM ION, ZINC ION, ... (5 entities in total)
• 機能のキーワード: pde5a, inhibitor, complex structure, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40622.37

構造登録者

Zhang, X.L.,Xu, Y.C. (登録日: 2018-12-05, 公開日: 2019-12-11, 最終更新日: 2024-03-27)

主引用文献

Wang, Z.,Jiang, X.,Zhang, X.,Tian, G.,Yang, R.,Wu, J.,Zou, X.,Liu, Z.,Yang, X.,Wu, C.,Shi, J.,Li, J.,Suo, J.,Wang, Y.,Zhang, R.,Xu, Z.,Gong, X.,He, Y.,Zhu, W.,Aisa, H.A.,Jiang, H.,Xu, Y.,Shen, J.
Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension.
J.Med.Chem., 62:4979-4990, 2019

PubMed Abstract: Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.

PubMed: 31021628
DOI: 10.1021/acs.jmedchem.9b00123

実験手法

X-RAY DIFFRACTION (2.155 Å)