Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators

被引：19

作者：

Greig, Iain R. ^{[1
]}

Baillie, Gemma L. ^{[1
,2
,3
]}

Abdelrahman, Mostafa ^{[4
,5
]}

Trembleau, Laurent ^{[4
]}

Ross, Ruth A. ^{[1
,2
,3
]}

机构：

[1] Univ Aberdeen, Inst Med Sci, Kosterlitz Ctr Therapeut, Aberdeen AB25 2ZD, Scotland

[2] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada

[3] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Toronto, ON M5S 1A8, Canada

[4] Univ Aberdeen, Sch Nat & Comp Sci, Lab Supramol Chem, Aberdeen AB24 3UE, Scotland

[5] Al Azhar Univ, Fac Pharm, Dept Organ Pharmaceut Chem, Assiut 71524, Egypt

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 18期

基金：

英国生物技术与生命科学研究理事会;

关键词：

Cannabinoid; Negative allosteric modulator; CB1; NAM; Indole sulfonamide; CB1; RECEPTORS; INDOLE-2-CARBOXAMIDES; FUNCTIONALITIES; ANTAGONIST; SYSTEM;

D O I：

10.1016/j.bmcl.2016.08.018

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes. In spite of the theoretical potential of CB1 NAMs, published in vivo studies have generally not been able to demonstrate the expected therapeutically-relevant CB1-mediated effects. Thus, a greater range of molecular tools are required to allow definitive elucidation of the effects of CB1 allosteric modulation. In this study, we show a novel series of indole sulfonamides. Compounds 5e and 6c (ABD1075) had potencies of 4 and 3 nM respectively, and showed good oral exposure and CNS penetration, making them highly versatile tools for investigating the therapeutic potential of allosteric modulation of the cannabinoid system. Crown Copyright (C) 2016 Published by Elsevier Ltd. All rights reserved.

引用

页码：4403 / 4407

页数：5

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