Ukita T, Nakamura Y, Kubo A, Yamamoto Y, Moritani Y, Saruta K, Higashijima T, Kotera J, Takagi M, Kikkawa K, Omori K
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa, Osaka 532-8505, Japan.
J Med Chem. 2001 Jun 21;44(13):2204-18. doi: 10.1021/jm000558h.
A novel class of potent and selective phosphodiesterase 5 (PDE5) inhibitors, 4-aryl-1-isoquinolinone derivatives, which have been designed by the comparison of the structure of cGMP and a previously reported 1-arylnaphthalene lignan, was disclosed. Among these compounds, methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate dihydrochloride (36a) exhibited potent PDE5 inhibitory activity (IC(50) = 1.0 nM) with high isozyme selectivities (IC(50) ratio: PDE1/PDE5 = 1300, PDE2/PDE5 > 10 000, PDE3/PDE5 > 10 000, PDE4/PDE5 = 4700, PDE6/PDE5 = 28). Compound 36a also showed the most potent relaxant effect on isolated rabbit corpus cavernosum (EC(30) = 7.9 nM). Compound 63 (T-1032), the sulfate form of 36a, was selected for further biological and pharmacological evaluation of erectile dysfunction.
一类新型的强效且选择性的磷酸二酯酶5（PDE5）抑制剂——4-芳基-1-异喹啉酮衍生物被公开，其是通过比较环鸟苷酸（cGMP）的结构与先前报道的1-芳基萘木脂素的结构而设计的。在这些化合物中，2-(4-氨基苯基)-1,2-二氢-1-氧代-7-(2-吡啶基甲氧基)-4-(3,4,5-三甲氧基苯基)-3-异喹啉羧酸甲酯二盐酸盐（36a）表现出强效的PDE5抑制活性（IC(50) = 1.0 nM），且具有高同工酶选择性（IC(50)比值：PDE1/PDE5 = 1300，PDE2/PDE5 > 10000，PDE3/PDE5 > 10000，PDE4/PDE5 = 4700，PDE6/PDE5 = 28）。化合物36a对离体兔海绵体也显示出最强的舒张作用（EC(30) = 7.9 nM）。化合物63（T-1032），即36a的硫酸盐形式，被选用于勃起功能障碍的进一步生物学和药理学评估。
