title: Exploration of the 5-bromopyrimidin-4(3H)-ones as potent inhibitors of PDE5.
abstract: The substituents both at the 6-position of the 5-bromopyrimidinone ring and at the 5'-position of the phenyl ring of 5-bromopyrimidin-4(3H)-ones were explored. 5-Bromo-6-isopropyl-2-(2-propoxy-phenyl)pyrimidin-4(3H)-one was identified as a new scaffold for potent PDE5 inhibitors. The crystal structures of PDE5/2e and PDE5/10a complexes provided a structural basis for the inhibition of 5-bromopyrimidinones to PDE5. In addition, it was also found that there is a great tolerance for the substitution at the 5'-position of the phenyl ring of 5-bormopyrimidinones and the resulted compound 13a has the highest inhibition activity to PDE5 (IC50, 1.7 nM).
authors.affiliation: Key Laboratory of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumiqi 830011, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Gong
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Ren
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Tiantian
authors.initials: T
authors.lastname: Chen
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yang
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Jiang
authors.forename: Jingshan
authors.initials: J
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Haji Akber
authors.initials: HA
authors.lastname: Aisa
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
mesh_terms: D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry / Q000378:metabolism; D054879:Halogenation; D006801:Humans; D008958:Models, Molecular; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D011743:Pyrimidines; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5
keywords: 5-Bromopyrimidin-4(3H)-ones; PDE5 inhibitors