Design and synthesis of novel 5-(3,4,5-trimethoxybenzoyl)-4-aminopyrimidine derivatives as potent and selective phosphodiesterase 5 inhibitors: Scaffold hopping using a pseudo-ring by intramolecular hydrogen bond formation

Abstract 5-(3,4,5-Trimethoxybenzoyl)-4-amimopyrimidine derivatives were found as a novel chemical class of potent and highly selective phosphodiesterase 5 inhibitors. A pseudo-ring formed by an intramolecular hydrogen bond constrained the conformation of 3-chloro-4-methoxybenzylamino and 3,4,5-trimethoxybenzoyl substituents and led to the discovery of T-6932 ( 19a ) with a potent PDE5 inhibitory activity (IC 50  = 0.13 nM) and a high selectivity over PDE6 (IC 50 ratio: PDE6/PDE5 = 2400). Further modification at the 2-position of T-6932 resulted in the finding of 26 , which exhibited potent relaxant effects on isolated rabbit corpus cavernosum (EC 30  = 11 nM) with a high PDE5 selectivity over PDE6 (IC 50 ratio: PDE6/PDE5 = 2800).