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

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.