Combined FAAH and COX inhibition by Flurbiprofen amide derivatives for the treatment of pain and inflammation

Nonsteroidal anti‐inflammatory drugs (NSAIDs) – such as ibuprofen and flurbiprofen – are non-selective COX inhibitors widely used to treat acute and chronic pain. Several studies have indicated that the analgesic effect of NSAIDs is enhanced when administered in combination with drugs that inhibit also the fatty acid amide hydrolase (FAAH) [1], an enzyme that degrades endocannabinoid anandamide (AEA), greatly decreasing the severity of GI side effects. From these evidences, arised the rational basis for the design of multi-target FAAH/COX inhibitors [2]. A series of ibuprofen and flurbiprofen amides derivatives have been previously designed as dual FAAH/COX inhibitors and, among them, ibu-am5 and flu-am1 revealed an interesting dual-action, retaining similar COX-inhibitory properties and an increased inhibition of FAAH than the parent compounds [3]. Here, we present the design, molecular modelling and in vitro and in vivo evaluation of a small series of flu-am1 analogs (Figure 1) with an increased dual FAAH/COX inhibition as promising compounds in the treatment of pain and inflammation.