T 0156 hydrochloride

T-0156, a novel phosphodiesterase type 5 inhibitor, and sildenafil have different pharmacological effects on penile tumescence and electroretinogram in dogs.[Pubmed:14757152]

Eur J Pharmacol. 2004 Feb 6;485(1-3):283-8.

T-0156 (2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)meth oxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride) is a newly synthesized phosphodiesterase type 5 inhibitor, and its potency and selectivity are higher than those of sildenafil in an enzyme assay. In the present study with anesthetized dogs, we examined the effects of intravenous T-0156 or sildenafil on the pelvic nerve stimulation-induced penile tumescence and light-adapted flicker stimulation-induced electroretinogram, parameters of which are reported to be indicators for inhibition of phosphodiesterase type 5 and type 6, respectively. Both compounds potentiated the penile tumescence in a dose-dependent manner. T-0156 at 10 microg/kg and sildenafil at 100 microg/kg showed almost the same potentiating percentage (181.5+/-31.1% and 190.0+/-37.9%) in spite of the plasma concentration of T-0156 being about five times lower than that of sildenafil (16.7+/-1.6 and 78.8+/-5.3 ng/ml), indicating that the effect of T-0156 on tumescence is more potent than that of sildenafil. While the high dose of T-0156 (1000 microg/kg) reduced the amplitude and increased the latency of the electroretinogram positive wave, the effects of T-0156 were conversely weaker than those of sildenafil (reduction of amplitude; T-0156: 41.1+/-8.0%, sildenafil: 71.7+/-3.9%, increase of latency; T-0156: 3.9+/-0.6%, sildenafil: 14.5+/-1.4%, at 1000 microg/kg). These results clearly showed the difference in the properties of T-0156 and sildenafil in pharmacological studies with anesthetized dogs, and the difference appeared to correspond with their inhibitory potencies for phosphodiesterase type 5 and type 6. It was concluded that T-0156 would be a useful pharmacological tool as a potent and highly selective phosphodiesterase type 5 inhibitor.

Enzymological and pharmacological profile of T-0156, a potent and selective phosphodiesterase type 5 inhibitor.[Pubmed:12450574]

Eur J Pharmacol. 2002 Dec 5;456(1-3):91-8.

The enzymological and pharmacological properties of 2-(2-Methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)metho xy-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 (IC(50)=0.23 nM), in a competitive manner. T-0156 also inhibited phosphodiesterase type 6 with IC(50) 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 (IC(50)>10 microM). 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 microg/kg potentiated the pelvic nerve stimulation-induced tumescence in anesthetized dogs (1000 microg/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.