4-（3-氯-4-甲氧基苄基）氨基酞嗪：合成及其对磷酸二酯酶5的抑制活性

4-(3-Chloro-4-methoxybenzyl)aminophthalazines: synthesis and inhibitory activity toward phosphodiesterase 5.

作者信息

Watanabe N, Adachi H, Takase Y, Ozaki H, Matsukura M, Miyazaki K, Ishibashi K, Ishihara H, Kodama K, Nishino M, Kakiki M, Kabasawa Y

机构信息

Tsukuba Research Laboratories, Eisai Company, Ltd., Tsukuba, Ibaraki, Japan.

出版信息

J Med Chem. 2000 Jun 29;43(13):2523-9. doi: 10.1021/jm9905054.

DOI:10.1021/jm9905054

PMID:10891111

Abstract

We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthala zinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC(50) = 0.56 nM) with >1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC(50) = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 microg/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.

摘要

我们合成了多种在1-位和6-位上有取代基的4-(3-氯-4-甲氧基苄基)氨基酞嗪，并评估了它们对磷酸二酯酶5（PDE5）的抑制活性以及在前列腺素F2α（10^(-5) M）预收缩的离体猪冠状动脉中的血管舒张活性。酞嗪1-位上的优选取代基为4-羟基哌啶基、4-羟甲基哌啶基、4-(2-羟乙基)哌啶基和4-氧代哌啶基。在这些化合物中，[4-(3-氯-4-甲氧基苄基)氨基-1-(4-羟基)哌啶基]-6-酞嗪甲腈盐酸盐（13）表现出强效的PDE5抑制活性（IC(50) = 0.56 nM），对其他PDE同工酶（PDE1-4）的选择性高1700倍以上。在这一系列化合物中，化合物13表现出最强的血管舒张作用（EC(50) = 13 nM）。以30 μg/kg静脉注射给慢性低氧大鼠时，化合物13可使平均肺动脉压降低29.9 +/- 3.1%，在大鼠中的口服生物利用度约为19.5%，因此被选用于进一步的生物学评估。