Conformational Restriction Leading to a Selective CB 2 Cannabinoid Receptor Agonist Orally Active Against Colitis

Jamal El Bakali (1) , Giulio G. Muccioli (2) , Mathilde Body-Malapel (3) , Madjid Djouina (3) , Frédérique Klupsch (1) , Alina Ghinet (1) , Amelie Barczyk (1) , Nicolas Renault (1) , Philippe Chavatte (1) , Pierre Desreumaux (3) , Didier Lambert (2) , Régis Millet (1)

1 ICPAL - Institut de Chimie Pharmaceutique Albert Lespagnol
2 UCL - Université Catholique de Louvain = Catholic University of Louvain
3 LIRIC - Lille Inflammation Research International Center - U 995

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.

Domaines: Chimie; Sciences du Vivant [q-bio]

Jamal El Bakali, Giulio G. Muccioli, Mathilde Body-Malapel, Madjid Djouina, Frédérique Klupsch, et al.. Conformational Restriction Leading to a Selective CB 2 Cannabinoid Receptor Agonist Orally Active Against Colitis. ACS Medicinal Chemistry Letters, 2015, 6 (2), pp.198 - 203. ⟨10.1021/ml500439x⟩. ⟨hal-01935803⟩