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, 1.7nM). [Copyright &y& Elsevier]