构象限制导致一种对结肠炎具有口服活性的选择性CB2大麻素受体激动剂。
Conformational Restriction Leading to a Selective CB2 Cannabinoid Receptor Agonist Orally Active Against Colitis.
作者信息
El Bakali Jamal, Muccioli Giulio G, Body-Malapel Mathilde, Djouina Madjid, Klupsch Frédérique, Ghinet Alina, Barczyk Amélie, Renault Nicolas, Chavatte Philippe, Desreumaux Pierre, Lambert Didier M, Millet Régis
机构信息
Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille Nord de France , E.A 4481, IFR 114, 3 rue du Pr. Laguesse, B.P. 83, F-59006 Lille Cedex, France.
Unité de Chimie Pharmaceutique et de Radiopharmacie, Louvain Drug Research Institute, Université catholique de Louvain , 73 avenue E. Mounier UCL-CMFA (7340), B-1200 Bruxelles, Belgium.
出版信息
ACS Med Chem Lett. 2014 Dec 4;6(2):198-203. doi: 10.1021/ml500439x. eCollection 2015 Feb 12.
Abstract
The CB2 cannabinoid receptor has been implicated in the regulation of intestinal inflammation. Following on from the promising activity of a series of 4-oxo-1,4-dihydroquinoline-3-carboxamide, we developed constrained analogues based on a 2H-pyrazolo[4,3-c]quinolin-3(5H)-one scaffold, with improved affinity for the hCB2 receptor and had very high selectivity over the hCB1 receptor. Importantly, the lead of this series (26, hCB2: K i = 0.39 nM, hCB1: K i > 3000 nM) was found to protect mice against experimental colitis after oral administration.
摘要
CB2大麻素受体与肠道炎症的调节有关。基于一系列4-氧代-1,4-二氢喹啉-3-甲酰胺的良好活性，我们开发了基于2H-吡唑并[4,3-c]喹啉-3(5H)-酮骨架的受限类似物，其对hCB2受体具有更高的亲和力，并且对hCB1受体具有非常高的选择性。重要的是，该系列的先导化合物（26，hCB2：Ki = 0.39 nM，hCB1：Ki > 3000 nM）经口服给药后被发现可保护小鼠免受实验性结肠炎的侵害。
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