Design, synthesis and biological activity of rigid cannabinoid CB1 receptor antagonists

被引：59

作者：

Stoit, AR ^{[1
]}

Lange, JHM ^{[1
]}

den Hartog, AP ^{[1
]}

Ronken, E ^{[1
]}

Tipker, K ^{[1
]}

van Stuivenberg, HH ^{[1
]}

Dijksman, JAR ^{[1
]}

Wals, HC ^{[1
]}

Kruse, CG ^{[1
]}

机构：

[1] Solvay Pharmaceut Res Labs, NL-1380 DA Weesp, Netherlands

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 2002年 / 50卷 / 08期

关键词：

benzocycloheptapyrazole; CB1 receptor antagonist; molecular modeling; regiochemistry;

D O I：

10.1248/cpb.50.1109

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated alpha,gamma-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pK(i)=7.2) as well as very potent antagonistic activity (pA(2)=8.8) in vitro. The regioselectivity of the pyrazole ring closure is shown to depend strongly on the aromatic substitution pattern of the applied arylhydrazine.

引用

页码：1109 / 1113

页数：5

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