Design, Synthesis, and Pharmacological Evaluation of Monocyclic Pyrimidinones as Novel Inhibitors of PDE5

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10540-10550
• 全文大小：441K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

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.