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

被引：25

作者：

Mochida, H ^{[1
]}

Takagi, M ^{[1
]}

Inoue, H ^{[1
]}

Noto, T ^{[1
]}

Yano, K ^{[1
]}

Fujishige, K ^{[1
]}

Sasaki, T ^{[1
]}

Yuasa, K ^{[1
]}

Kotera, J ^{[1
]}

Omori, K ^{[1
]}

Kikkawa, K ^{[1
]}

机构：

[1] Tanabe Seiyaku Co Ltd, Discovery Res Labs, Toda, Saitama 3358505, Japan

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2002年 / 456卷 / 1-3期

关键词：

T-0156; phosphodiesterase isozyme; phosphodiesterase type 5 inhibitor; cyclic guanosine monophosphate; corpus cavernosum; tumescence;

D O I：

10.1016/S0014-2999(02)02590-6

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：91 / 98

页数：8

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