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  • br Acknowledgment br Introduction Non steroidal anti inflamm


    Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are widely utilized to treat pain and inflammation [1], but their chronic use is hindered by a variety of potentially serious adverse events that include gastrointestinal (GI) mucosal lesions, bleeding and perforations [2], [3], [4], [5]. 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) [6]. 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 [7], [8], [9], [10]. 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 [6]. Nevertheless, the use of COX-2 inhibitors has been linked to a distinctive set of adverse cardiovascular effects [11], [12]. 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 [13], [14], [15]. Agents designed to achieve this objective include nitric oxide (NO) donors-NSAIDs [16], [17], COX-2 inhibitors–NO–donors [18], [19], hydrogen sulfide (H2S) donors-NSAIDs [20], [21], [22], as well as compounds that block distinct enzymes of the AA pathway, such as COX/lipoxygenase [23], [24] and COX-2/soluble epoxy hydrolase (sEH) [25]. Another potential multitarget strategy to treat inflammation is the concomitant inhibition of COX and fatty acid amide hydrolase (FAAH) [26][27], [28], [29], [30], [31], [32], [33], 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 [34], [35]. These lipid mediators include the endocannabinoid anandamide (arachidonoylethanolamide) – which engages cannabinoid-1 (CB1) and CB2 receptors to suppress neutrophil migration [36] and prevent immune-cell recruitment [37], [38] – as well as the endogenous peroxisome proliferator-activate receptor-α (PPAR-α) agonists, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) [39], [40], [41]. In addition to opposing pain and inflammation, these FAAH substrates are also protective of the GI mucosa [42], [43]. 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 [44], [45], [46]. In several chronic inflammatory conditions, including inflammatory bowel disease (IBD), FAAH [47], [48], [49] and COX-2 [50] 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) [51]. This scaffold merges key pharmacophores of two known classes of FAAH and COX inhibitors – O-aryl carbamates [52], [53], [54], [55], [56], [57], [58] such as [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597, 2) [54], [57], and 2-aryl propionic acids [6] such as flurbiprofen, 3a[59], [60], [61] – 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[53], [54], [56] and the ether moieties of 3b or 3c[61], respectively (Fig. 1).