title: Design, synthesis, and pharmacological evaluation of monocyclic pyrimidinones as novel inhibitors of PDE5.
abstract: 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.
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Tiantian
authors.initials: T
authors.lastname: Chen
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
authors.forename: Jing
authors.initials: J
authors.lastname: Ren
authors.forename: Guanghui
authors.initials: G
authors.lastname: Tian
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Suo
authors.forename: Rongxia
authors.initials: R
authors.lastname: Zhang
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Jiang
authors.forename: Nicholas Kenneth
authors.initials: NK
authors.lastname: Terrett
authors.forename: Jingshan
authors.initials: J
authors.lastname: Shen
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D020134:Catalytic Domain; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry / Q000187:drug effects*; D015195:Drug Design; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; D011744:Pyrimidinones; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5