1,7- and 2,7-naphthyridine derivatives as potent and highly specific PDE5 inhibitors

Abstract Novel 1,7- and 2,7-naphthyridine derivatives, designed by the introduction of nitrogen atom into the phenyl ring of previously reported 4-aryl-1-isoquinolinone derivatives, were disclosed as a new structural class of potent and specific PDE5 inhibitors. Among them, 2,7-naphthyridine 4c showed potent PDE5 inhibition (IC 50 =0.23 nM) and one of the best PDE5 specificities against PDEs1–4,6 (>100,000-fold selective versus PDE1–4, 240-fold selective vs PDE6). This compound showed more potent relaxant effects on isolated rabbit corpus cavernosum (EC 30 =5.0 nM) than Sildenafil (EC 30 =8.7 nM). The compound 4c (T-0156) was selected for further biological and pharmacological evaluation of erectile dysfunction.