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Publication Abstract from PubMed

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.

Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5.,Wang G, Liu Z, Chen T, Wang Z, Yang H, Zheng M, Ren J, Tian G, Yang X, Li L, Li J, Suo J, Zhang R, Jiang X, Terrett NK, Shen J, Xu Y, Jiang H J Med Chem. 2012 Dec 13;55(23):10540-50. doi: 10.1021/jm301159y. Epub 2012 Nov, 19. PMID:23137303^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.