Fatty acid amide hydrolase (FAAH) is an intracellular amidase signature family of serine hydrolases enzyme, which catalyzes the hydrolysis of bioactive fatty acid ethanolamides such as anandamide and oleoylethanolamide. FAAH serves as the major metabolic regulator of many of the endogenous fatty acid amides, exhibiting a distribution consistent with its role in terminating their effects at the released sites of action. It is the only well characterized mammalian enzyme bearing their unusual Ser–Ser–Lys catalytic triad.
A remarkable series of potent, selective, and efficacious inhibitors of the enzyme FAAH have now been disclosed, many of which have been utilized to mechanistically and structurally characterize the enzyme. In this regard, it is interesting to note that around 70 million Americans annually suffer from chronic disorders in sleep, making sleep second only to pain in the number of patients seeking medical attention.
Several studies summarized in recent reviews have detailed the discovery of FAAH and defined its potential to serve as a new therapeutic target for the treatment of a range of clinical disorders. The development of inhibitors of FAAH, the enzyme responsible for degradation of endogenous oleamide and anandamide and may prove to be useful therapeutic agents for the treatment of sleep disorders and pain.
Since FAAH is recognized as a drug target, a large number of inhibitors have been synthesized and tested since 1994, and these are reviewed in terms of reversibility, potency, and specificity for FAAH and cannabinoid receptors. An innovative clinical opportunity likely will emerge, from better understanding the fundamental physiological role of the signaling fatty acid amides, which FAAH regulates. This area is still incompletely defined.
Inhibitors of FAAH are considered a potential therapeutic approach, for the treatment of several nervous system disorders, including pain, anxiety, and insomnia. However, for FAAH inhibitors to achieve clinical utility, they must not only display efficacy in vivo but also selectivity for this enzyme relative to the numerous other serine hydrolases present in mammalian proteomes.
Figure 1: Mechanism of Fatty Acid Amide Hydrolase
“The FAAH Inhibitors – Pipeline Insights, 2015” report, provides information of 25+ pipeline drugs with 13+ companies actively involved in drug development. There are 3 drugs in phase II, 2 in phase I, 4 in pre-clinical, 1 in discovery, 14 in inactive and 1 in discontinued. Vernalis plc is developing a lead product V-158866 which is in Phase II.
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