1-arylnaphthalene lignan: A novel scaffold for type 5 phosphodiesterase inhibitor

1-Arylnaphthalene lignan, which had been reported as a PDE4 inhibitor by Iw asaki, was disclosed as a new structural class of PDE5 inhibitors. The stru ctural requirements for potent and specific PDE5 inhibition were revealed i n a 1-arylnaphthalene lignan series, in which 1-(3-bromo-4, 5-dimethoxyphen yl)-5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-2-(methoxycarbony l)naphthalene hydrochloride (27q) showed the most potent and specific inhib ition (PDE5 inhibition IC50 = 6.2 nM, selectivity for PDE5 against PDE1, -2 , -3, and -4 > 16 000). It is noteworthy that 27q has the best selectivitie s against PDE isoforms among PDE5 inhibitors so far reported. Compound 27q exhibited almost the same relaxant effects on rat aortic rings as sodium 1- [6-chloro-4-[(3,4-methylenedioxybenzyl)amino]quinazolin-2-yl]piperidine-4-c arboxylate (35) (27q, EC50 = 0.10 mu M; 35, EC50 = 0.20 mu M) and was selec ted for further biological evaluation.