New FAAH inhibitors based on 3-carboxamido-5-aryl-isoxazole scaffold that protect against experimental colitis Virginie Andrzejak a , Giulio G. Muccioli b,e , Mathilde Body-Malapel c , Jamal El Bakali a , Madjid Djouina c , Nicolas Renault d , Philippe Chavatte d , Pierre Desreumaux c , Didier M. Lambert e , Régis Millet a,⇑ a Université Lille Nord de France, ICPAL, EA 4481, IFR114, 3 rue du Professeur Laguesse, BP-83, F-59006 Lille, France b Université Catholique de Louvain, Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids Lab, 72 Avenue E. Mounier (CHAM7230), B-1200 Bruxelles, Belgium c Université Lille Nord de France, INSERM U995, Faculté de Médecine, Amphi J & K, IFR114, Boulevard du Professeur Leclercq, F-59045 Lille, France d Université Lille Nord de France, Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Chimie Thérapeutique, EA 4481, IFR 114, 3 rue du Professeur Laguesse, BP-83, F-59006 Lille, France e Université catholique de Louvain, Louvain Drug Research Institute, Unité de Chimie Pharmaceutique et de Radiopharmacie, 73 Avenue E. Mounier UCL (CMFA7340), B-1200 Bruxelles, Belgium article info Article history: Received 10 February 2011 Revised 26 April 2011 Accepted 30 April 2011 Available online 6 May 2011 Keywords: FAAH Cannabinoids IBD Isoxazole FAAH modeling abstract Growing evidence suggests a role for the endocannabinoid (EC) system, in intestinal inflammation and compounds inhibiting anandamide degradation offer a promising therapeutic option for the treatment of inflammatory bowel diseases. In this paper, we report the first series of carboxamides derivatives pos- sessing FAAH inhibitory activities. Among them, compound 39 displayed significant inhibitory FAAH activity (IC 50 = 0.088 lM) and reduced colitis induced by intrarectal administration of TNBS. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Endocannabinoids (ECs), including anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are arachidonic acid derived bioac- tive lipids that are biosynthesized on demand, and which, following the activation of both cannabinoid receptors (CB 1 and CB 2 ) trigger a wide range of biological responses. These physiological effects are transient due to a rapid inactivation of ECs by specific enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). 1–4 In the gastrointestinal tract, these endogenous ligands control, notably via CB 1 and/or CB 2 receptor activation, many physiological functions including intestinal motility, secretion and inflammation. 5 Accordingly, stimulation of cannabinoid receptors directly or indirectly constitutes a promising strategy to treat several gastroin- testinal pathologies, especially diseases wherein an inflammatory process is involved such as, for example, inflammatory bowel diseases. For that matter, increased levels of AEA as well as up-regula- tion of cannabinoid receptors expression were reported during intestinal inflammation, 6–8 and described as a protective mecha- nism to counteract inflammation. 9 Over the past few years sev- eral studies have provided evidence that exogenous agonists acting at CB 1 and/or CB 2 receptors, as well as inhibitors of EC re-uptake and degradation, provide protection against experimen- tal colitis. 10–12 Indeed, it has been shown that the nonselective cannabinoid receptor agonist HU210 as well as the two selective CB 2 receptor agonist JWH133 and AM1241 are able to signifi- cantly reduce inflammation in hapten-induced colitis in mice. 10 Consistent with these results, both genetic and pharmacological blockade of either CB 1 or CB 2 receptor signaling led to a worsen- ing of colitis in these experimental models. 10 Another approach consisting in raising anandamide levels has been successfully ap- plied to reduce intestinal inflammation by using inhibitors of EC membrane transport (VDM11) or FAAH (URB597). 11 The involve- ment of both cannabinoid receptors was confirmed by performing experiments in CB 1 and CB 2 knock out mice. Targeting FAAH is of particular interest since it increases AEA, and related N-acylethanolamines, levels without triggering 0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2011.04.057 ⇑ Corresponding author. Tel.: +33 320964374; fax: +33 320964906. E-mail address: regis.millet@univ-lille2.fr (R. Millet). Bioorganic & Medicinal Chemistry 19 (2011) 3777–3786 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc