FAAH inhibitor

Neuropathic pain Endocannabinoid levels are elevated in FAAH inhibitors... 

FAAH was originally purified and cloned from rat liver microsomes and is able to catalyse the hydrolysis of anandamide and 2-AG, in addition to other long-chain fatty acid amides [25]. Studies into the structure and role of this enzyme have generated interest in the potential therapeutic applications of FAAH inhibitors [26-28]. FAAH knock-out mouse brains contained 15-fold higher levels of anandamide than their wild-type counterparts and these animals have also been shown to be more responsive to exogenously administered anandamide [29]. These animals also showed a reduced response to painful stimuli, supporting the hypothesis that FAAH inhibition may provide novel analgesics. Levels of 2-AG were not elevated in the FAAH knock-out animals, apparently due to the existence of alternative metabolic fates for this compound [30]. 

The Boger group [64-66] has extensively studied the use of a-ketoheterocycles as FAAH inhibitors. In their initial studies, a range of a-ketoheterocycles based on oleic acid was synthesised. A range of five- and six-membered monocyclic heterocycles and three bicyclic heterocycles (benzothiazole, benzimidazole and benzoxazole) was examined. Although many of the compounds tested were found to inhibit FAAH activity with micromolar affinities, the best results were obtained with heterocycles that incorporated a weakly basic nitrogen a - to the heterocycle (Table 6.5) [64]. 

Bristol-Myers Squibb has recently disclosed two different series of carbamate-based FAAH inhibitors. The first of these is a series of 4,5-diaryl-imidazoles in which 30 compounds are specifically claimed, an example being compound (57). This compound is reported to have an IC50 value of < 10 nM. In addition, (57) was also active in vivo in rodent models of chemo-induced, thermal and neuropathic pain [72]. The second series of compounds is based on oxime carbamoyl FAAH inhibitors such as (58). Compound (58) is reported to have an IC50 value of < 10 nM and activity in rodent models of inflammatory pain, thermal pain and inflammatory oedema [73]. 

A series of palmitoylethanolamine-derived inhibitors has been described in the literature as FAAH inhibitors [77, 78]. This study explored the effect of shortening the chain length and replacement of the ethanolamine head group with primary, secondary and tertiary amide alternatives. Of the compounds synthesised and tested, two compounds gave reasonable affinities for FAAH inhibition, palmitoyl-isopropylamide (63) (IC50 = 13/rM) and palmitoyl-allylamide (64) (IC50 = 3.4/rM). Both these compounds had little affinity for either CBi or CB2 receptors. 

Finally, derivatives of the endogenous compound 2-octyl- y-bromoacetate (65) have been reported as FAAH inhibitors [79]. In a limited SAR study, it was found that replacement of the bromine with a chlorine atom had little effect on affinity. The replacement of the alkyl chain with oleyl-chain mimics resulted in an increase of affinity for FAAH (approximately 5-fold). The removal of the halogen and replacement with either a proton or methyl resulted in inactive compounds. The most potent compound identified in this series was compound (66) with an IC50 value of 0.6/rM [79]. 

A competitive version of ABPP identifies the target(s) and assesses the selectivity of an enzyme inhibitor in biological systems by gauging how well the inhibitor slows the enzyme s reaction with an ABP. For example, fluorophosphonate ABP 3 was used to profile the selectivity of fatty acid amide hydrolase (FAAH) inhibitors within the serine hydrolase superfamily [27] (FAAH hydrolyzes endocannabinoids such as anandamide). Serine hydrolases that exhibited reduced labeling by the probe in the presence of inhibitor were scored as targets of the inhibitor. Urea FAAH inhibitors exemplified by PF-3845 (5) that covalently modify the active-site serine nucleophile of FAAH were found to be exquisitely selective for FAAH in brain and liver... 

Endocannabi- AM 404 Transport/FAAH inhibitor 1 pM at transporter (IC50)... 

AEA and 2-AG Hydolyzing Palmitoyliso- propylamide FAAH Inhibitor 10pM(IC50)... 

A number of inhibitors of FAAH have been synthesized (207), and the more potent of these are depicted in Fig. 5.16. The most potent compounds contain a highly electrophilic carbonyl as part of either an a-ketoester, a-ke-toamide of trifluoromethyl ketone moiety, structural features common to serine/cysteine protease inhibitors. Several of these FAAH inhibitors caused sleep enhancement and lowering of body temperature in rats that were comparable with those induced by oleamide. Based on these findings, it has been suggested that FAAH may represent a therapeutic target for... 

FAAH inhibitors enhance, and anandamide uptake inhibitors inhibit, anandamide accumulation into some cells (Kathuria et al. 2003). 

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