4G2W

Crystal structure of PDE5A in complex with its inhibitor

4G2W の概要

• エントリーDOI: 10.2210/pdb4g2w/pdb
• 関連するPDBエントリー: 4G2Y
• 分子名称: cGMP-specific 3',5'-cyclic phosphodiesterase, 5,6-diethyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]-2-propoxyphenyl}pyrimidin-4(3H)-one, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: phosphodiesterase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 40735.50

構造登録者

Ren, J.,Chen, T.T.,Xu, Y.C. (登録日: 2012-07-13, 公開日: 2013-06-26, 最終更新日: 2023-11-08)

主引用文献

Wang, G.,Liu, Z.,Chen, T.T.,Wang, Z.,Yang, H.,Zheng, M.,Ren, J.,Tian, G.,Yang, X.,Li, L.,Li, J.,Suo, J.,Zhang, R.,Jiang, X.,Terrett, N.K.,Shen, J.,Xu, Y.C.,Jiang, H.
Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5.
J.Med.Chem., 55:10540-10550, 2012

PubMed Abstract: Cyclic nucleotide phosphodiesterase type 5 (PDE5) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC50 ranging from 1 to 100 nM and 11 compounds with IC50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2-[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]pyrimid-4(3H)-one, the most potent compound, has an excellent IC50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.

PubMed: 23137303
DOI: 10.1021/jm301159y

実験手法

X-RAY DIFFRACTION (2.28 Å)