New FAAH inhibitors based on 3-carboxamido-5-aryl-isoxazole scaffold that protect against experimental colitis

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…colitis in mice at a 10 mg/kg oral dose. 112 The molecular modeling of compound 80 suggested that its isoxazole and carboxamide moieties interact with the oxyanion hole, and form hydrogen bonds with Ile138 and Lys142, respectively. The rigid biphenyl group was assumed to establish a π-π interaction with Phe194.…”

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…The beneficial effects of increased anandamide levels are CB 1 -and CB 2 -dependent because URB597 and VDM11 had no effect in CB 1 À/À or CB 2 À/À mice [55]. In addition, a newly described FAAH inhibitor, compound (39) in [67] (10 mg/kg, q.d. ), also reduced inflammation in TNBS-colitis, although its effects on anandamide levels or FAAH activity in vivo were not reported [67].…”

“…In addition, a newly described FAAH inhibitor, compound (39) in [67] (10 mg/kg, q.d. ), also reduced inflammation in TNBS-colitis, although its effects on anandamide levels or FAAH activity in vivo were not reported [67].…”

Animal Models of Colitis: Lessons Learned, and Their Relevance to the Clinic

“…(Andrzejak et al, 2011) DSS DSS makes the inner colon mucus layer permeable to bacteria, which reach the epithelial cells and trigger an inflammatory reaction. Altered inner colon mucus layer may be an early event in colitis development.…”

“…This is seen in the conclusions to many studies incorporating such models, or indeed articles reviewing the use of these models, which tend to finish with statements referring to future, rather than current, therapeutic advances. Some examples of such conclusions are as follows (note that italics are not in the original references): "...promising target for the Inflammatory Bowel Diseases (IBD) treatment" (Andrzejak et al, 2011); "substantial investment from the pharmaceutical industry should deliver novel therapies arising from gene discovery to the clinic within the next 5 years" ; "...recently established genetically engineered mouse models lacking IBD susceptibility gene should be promising tools to develop novel therapeutic measures for IBD" (Mizoguchi and Mizoguchi, 2010). This is not to detract from some excellent research in the field, and the recently established genetically engineered mouse models lacking IBD susceptibility genes should indeed prove to be promising tools to develop novel therapies.…”