jm301159y_si_001.pdf (5.9 MB)
Design, Synthesis, and Pharmacological Evaluation of Monocyclic Pyrimidinones as Novel Inhibitors of PDE5
journal contribution
posted on 2012-12-13, 00:00 authored by 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 JiangCyclic 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.