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