br Acknowledgment br Introduction Non steroidal anti inflamm
Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are widely utilized to treat pain and inflammation , but their chronic use is hindered by a variety of potentially serious adverse events that include gastrointestinal (GI) mucosal lesions, bleeding and perforations , , , . Conventional NSAIDs inhibit the two isoforms of cyclooxygenase (COX), COX-1 and COX-2, which catalyze the first committed steps in the biosynthetic pathway that converts arachidonic TMC647055 Choline salt australia (AA) into inflammatory prostanoids such as prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) . The dual role of COX-1-derived PGE2 as inflammation promoter and mucosal tissue protectant explains, at least in part, why NSAIDs cause damage to the GI tract , , , . Efforts to overcome this problem have led to the development of selective COX-2 inhibitors, which combine a high level of anti-inflammatory efficacy with a reduced propensity to cause injury to the GI mucosa . Nevertheless, the use of COX-2 inhibitors has been linked to a distinctive set of adverse cardiovascular effects , . Thus, the need for safe and effective drugs that can be used in the treatment of chronic inflammatory disorders remains urgent. A promising approach to meet this need is offered by targeting with a single agent more than one component of the inflammatory cascade , , . Agents designed to achieve this objective include nitric oxide (NO) donors-NSAIDs , , COX-2 inhibitors–NO–donors , , hydrogen sulfide (H2S) donors-NSAIDs , , , as well as compounds that block distinct enzymes of the AA pathway, such as COX/lipoxygenase ,  and COX-2/soluble epoxy hydrolase (sEH) . Another potential multitarget strategy to treat inflammation is the concomitant inhibition of COX and fatty acid amide hydrolase (FAAH) , , , , , , , a serine hydrolase that deactivates a family of analgesic and anti-inflammatory lipid amides that are produced by host-defense cells and other cells in the body , . These lipid mediators include the endocannabinoid anandamide (arachidonoylethanolamide) – which engages cannabinoid-1 (CB1) and CB2 receptors to suppress neutrophil migration  and prevent immune-cell recruitment ,  – as well as the endogenous peroxisome proliferator-activate receptor-α (PPAR-α) agonists, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) , , . In addition to opposing pain and inflammation, these FAAH substrates are also protective of the GI mucosa , . Indeed, studies in animal pain models have shown that co-administration of FAAH and COX inhibitors results in a synergistic potentiation of analgesia along with reduced gastric damage , , . In several chronic inflammatory conditions, including inflammatory bowel disease (IBD), FAAH , ,  and COX-2  are expressed at abnormally high levels. This simultaneous up-regulation may help establish a pathological state that exacerbates inflammation by amplifying inflammatory COX-dependent signals at the expense of defensive FAAH-regulated mediators. This hypothesis predicts that drugs targeting both COX and FAAH should have substantial anti-inflammatory efficacy combined with reduced GI toxicity. In a recent study, we provided support to this hypothesis using a multitarget modulator based on the hybrid scaffold 1 (Fig. 1) . This scaffold merges key pharmacophores of two known classes of FAAH and COX inhibitors – O-aryl carbamates , , , , , ,  such as [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597, 2) , , and 2-aryl propionic acids  such as flurbiprofen, 3a, ,  – which share a biphenyl core as a common structural motif (A and B rings, Fig. 1). Moreover, structure-activity relationship (SAR) studies of these scaffolds supported the hypothesis of additional elements of structural overlapping, such as the oxygenated substituents at the 3′-position of the A phenyl ring, corresponding to the carbamate functionality of 2, ,  and the ether moieties of 3b or 3c, respectively (Fig. 1).