A group of drugs that inhibit one or other of the two human fatty acid amide hydrolases. Challengingly other mammalian fatty acid amide hydrolases and associated signalling systems appear to have significant differences to those in man. The group is being developed as neuromodulators based on the hope that more selective inhibition of the degradation of endocannabinoids such as anandamide will avoid the systemic side effects of cannabinoids as manifest by cannabis (anti-nociception, hypothermia, hypolocomotion, catalepsy). Quite a wide range of chemicals have been found to have such properties but the quest for selectivity has had at least one notable disaster in a phase 1 trial of BIA 10-2474 in 2016. A range of properties of individual FAAH inhibitors has indeed been demonstrated in various animal models and man, with species variation in response and even abuse potential of some molecules complicating clinical development. Dual FAAH/MAGL inhibitors such as SA-57 are also in development as monoglyceride lipase (MAGL) is also important in endocannabinoid metabolism but has proved harder to target. Dual inhibition of COX 2 and FAAH has also been pursued.
- ↑ Vandevoorde S. Overview of the chemical families of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors. Current topics in medicinal chemistry. 2008; 8(3):247-67.
- ↑ Gamage TF, Ignatowska-Jankowska BM, Muldoon PP, Cravatt BF, Damaj MI, Lichtman AH. Differential effects of endocannabinoid catabolic inhibitors on morphine withdrawal in mice. Drug and alcohol dependence. 2015 Jan 1; 146:7-16.(Link to article – subscription may be required.)
- ↑ Rose TM, Reilly CA, Deering-Rice CE, Brewster C, Brewster C. Inhibition of FAAH, TRPV1, and COX2 by NSAID-serotonin conjugates. Bioorganic & medicinal chemistry letters. 2014 Dec 15; 24(24):5695-8.(Link to article – subscription may be required.)