Enzymological and pharmacological profile of T-0156, a potent and selective phosphodiesterase type 5 inhibitor

The enzymological and pharmacological properties of 2-(2-Methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T-0156), a new phosphodiesterase type 5 inhibitor, were studied in vitro and in vivo. The inhibitory effects of T-0156 on six phosphodiesterase isozymes isolated from canine tissues were investigated. T-0156 specifically inhibited the hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase type 5, at low concentration (IC50=0.23 nM), in a competitive manner. T-0156 also inhibited phosphodiesterase type 6 with IC50 value of 56 nM, which was 240-fold higher than that for inhibition of phosphodiesterase type 5. T-0156 had low potencies against phosphodiesterase types 1, 2, 3, and 4 (IC50>10 muM). In the isolated rabbit corpus cavernosum, T-0156 at 10 and 100 nM increased cGMP levels (100 nM T-0156-treated: 6.0 +/- 1.5 pmol/mg protein, vehicle-treated: 1.1 +/- 0.4 pmol/mg protein, P < 0.05), causing relaxation of the tissue. T-0156 at 1 to 100 nM potentiated the electrical field stimulation-induced relaxation in the isolated rabbit corpus cavernosum in a concentration-dependent manner (100 nM T-0156-treated: 76.9 +/- 19.8%, vehicle-treated: 12.3 +/- 10.1%, P < 0.05). Intraduodenal administration of T-0156 at 100 to 1000 mug/kg potentiated the pelvic nerve stimulation-induced tumescence in anesthetized dogs (1000 mug/kg T-0156-treated: 279.0 +/- 38.4%, vehicle-treated: 9.8 +/- 4.5%, P < 0.05). These results suggested that T-0156 enhanced the nitric oxide (NO)/cGMP pathway, probably through blockade of phosphodiesterase type 5 in vitro and in vivo experimental conditions. The present study clearly showed that T-0156 is a potent and highly selective phosphodiesterase type 5 inhibitor, which is a useful tool for pharmacological studies in vitro and in vivo. (C) 2002 Elsevier Science B.V. All rights reserved.