Discovery of 1,7-cyclized indoles as a new class of potent and highly selective human β3-adrenergic receptor agonists with high cell permeability

被引：24

作者：

Mizuno, K

Sawa, M

Harada, H

Taoka, I

Yamashita, H

Oue, M

Tsujiuchi, H

Arai, Y

Suzuki, S

Furutani, Y

Kato, S

机构：

[1] Dainippon Pharmaceut Co Ltd, Chem Res Labs, Suita, Osaka 5640053, Japan

[2] Dainippon Pharmaceut Co Ltd, Pharmacol & Microbiol Res Labs, Suita, Osaka 5640053, Japan

[3] Dainippon Pharmaceut Co Ltd, Pharmacokinet & Physicochem Property Res Labs, Suita, Osaka 5640053, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2005年 / 13卷 / 03期

关键词：

beta(3)-adrenergic receptor; agonist; 1,7-cyclized indole;

D O I：

10.1016/j.bmc.2004.10.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The synthesis and evaluation of a novel series of 1,7-cyclized indole-based human adrenergic receptor (beta(3)-AR) agonists are reported. The synthesis of a variety of 1,7-cyclized indole part was accomplished by the Mitsunobu reaction or a ring closing metathesis (RCM) reaction. SAR studies revealed that expansion of the ring size resulted in considerable selecurity against the beta(1)- and beta(2)-ARs. Compound 26, an eight-membered ring analogue with a double bond on its 1.7-linker portion, was found to be a potent beta(3)-AR agonist (EC50 = 0.75 nM, IA = 90%) with extremely high selectivity for the beta(3)-AR over the beta(1)- and beta(2)-ARs. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：855 / 868

页数：14

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