Novel, potent, and selective phosphodiesterase 5 inhibitors: Synthesis andbiological activities of a series of 4-aryl-1-isoquinolinone derivatives

A novel class of potent and selective phosphodiesterase 5 (PDE5) inhibitors , 4-aryl-1-iso-quinolinone derivatives, which have been designed by the com parison of the structure of cGMP and a previously reported 1-arylnaphthalen e lignan, was disclosed. Among these compounds, methyl 2-(4-aminophenyl)-1, 2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)- 3-isoqui noline carboxylate dihydrochloride (36a) exhibited potent PDE5 inhibitory a ctivity (IC50 = 1.0 nM) with high isozyme selectivities (IC50 ratio: PDE1/P DE5 = 1300, PDE2/PDE5 > 10 000, PDE3/PDE5 > 10 000, PDE4/PDE5 = 4700, PDE6/ PDE5 = 28). Compound 36a also showed the most potent relaxant effect on iso lated rabbit corpus cavernosum (EC30 = 7.9 nM). Compound 63 (T-1032), the s ulfate form of 36a, was selected for further biological and pharmacological evaluation of erectile dysfunction.