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ACS Med Chem Lett. 2014 Dec 4;6(2):198-203. doi: 10.1021/ml500439x. eCollection 2015 Feb 12.

Conformational Restriction Leading to a Selective CB2 Cannabinoid Receptor Agonist Orally Active Against Colitis.

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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.
Digestive inflammatory diseases: pathophysiology and development of therapeutic targets. U995 INSERM, Université Lille Nord de France, IFR 114, Amphis J & K, Boulevard du Professeur J. Leclercq, 59045 Lille Cedex, France.


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.


Cannabinoid receptor; colitis; conformational restriction; endocannabinoid; inflammatory bowel disease; quinolone

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