The first substrate analogue inhibitors of FAAH were reported in 1994. The anandamide analogues prepared represented three classes of putative transition-state inhibitors: a-trifluoromethyl ketones, a-ketoesters and a-ketoamides . In the initial screening studies, it was found that the trifluoromethyl ketone compounds tested were effective inhibitors of AEA hydrolysis. A selected set of a-keto esters also inhibited hydrolysis, while a-keto amides were ineffective. In particular, arachidonyl trifluoromethyl ketone (32), gave almost 100% inhibition of anandamide hydrolysis. A detailed investigation of the structural requirements for FAAH inhibition with a-trifluoromethyl ketones has been carried out by Boger and co-workers .
The electrophilic carbonyl is essential for activity; replacement with a methyl ketone results in complete loss of activity (Table 6.4, (33) and (34)). Saturated alkyl chains are tolerated but must be at least seven carbons long, shortening the chain length further results in dramatic losses of potency (Table 6.4, (36)-(39)). In contrast, extending the chain from seven through seventeen carbons has little effect on potency (Table 6.4, (36) and (38)). Incorporation of the oleamide A9,10 cis double bond is favoured with an almost 2-fold increase in potency compared to its saturated congener (cf. (33) and (36)), the trans isomer is also tolerated (Table 6.4, (35)). Replacement of the oleamide A9,10 cis double bond and alkyl tail with a phenyl group (Table 6.4, (40)) gives a further enhancement in affinity.
Table 6.4 FAAH INHIBITORS - TRIFLUOROMETHYL KETONES 
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