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

El Bakali, Jamal;Muccioli, Giulio;Body-Malapel, Mathilde;Djouina, Madjid;Millet, Régis;et.al.
(2015) ACS Medicinal Chemistry Letters — Vol. 6, n° 2, p. 198-203 (2015)

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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.
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El Bakali, J., Muccioli, G., Body-Malapel, M., Djouina, M., Klupsch, F., Ghinet, A., Barczyk, A., Renault, N., Chavatte, P., Desreumaux, P., Lambert, D., & Millet, R. (2015). Conformational Restriction Leading to a Selective CB2 Cannabinoid Receptor Agonist Orally Active Against Colitis. ACS Medicinal Chemistry Letters, 6(2), 198-203. https://doi.org/10.1021/ml500439x (Original work published 2015)