Design, Synthesis, and Pharmacological Evaluation of Monocyclic Pyrimidinones as Novel Inhibitors of PDE5 Guan Wang Zheng Liu Tiantian Chen Zhen Wang Huaiyu Yang Mingyue Zheng Jing Ren Guanghui Tian Xiaojun Yang Li Li Jianfeng Li Jin Suo Rongxia Zhang Xiangrui Jiang Nicholas Kenneth Terrett Jingshan Shen Yechun Xu Hualiang Jiang 10.1021/jm301159y.s001 https://acs.figshare.com/articles/journal_contribution/Design_Synthesis_and_Pharmacological_Evaluation_of_Monocyclic_Pyrimidinones_as_Novel_Inhibitors_of_PDE5/2460190 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(3<i>H</i>)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4­(3<i>H</i>)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC<sub>50</sub> ranging from 1 to 100 nM and 11 compounds with IC<sub>50</sub> ranging from 1 to 10 nM. Compound <b>5</b>, 5,6-diethyl-2-[2-<i>n</i>-propoxy-5-(4-methyl-1-piperazinylsulfonyl)­phenyl]­pyrimid-4­(3<i>H</i>)-one, the most potent compound, has an excellent IC<sub>50</sub> (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. 2012-12-13 00:00:00 compound cyclic guanosine monophosphate PDE 5 hydrolysis PDE 5Cyclic nucleotide phosphodiesterase type 5 nM IC 50 novel PDE 5 inhibitors