A new group of oxime carbamates as reversible inhibitors of fatty acid amide hydrolase

The discovery and development of inhibitors of fatty acid amide hydrolase (FAAH)

“…40 However, a second series of oxime carbamates has been identified as potent FAAH inhibitors, and were reported to behave as non-competitive (Lineweaver Burk analysis), but reversible FAAH inhibitors, exhibiting selectivity for FAAH over the other enzymes and receptors in the endocannabinoid system. 41 Enol carbamates have also been reported as analogous non-competitive (Lineweaver Burk analysis), but reversible FAAH inhibitors (Figure 11). 42 Although not yet demonstrated, it is hard to imagine that such classes do not acylate the FAAH catalytic Ser241 as their primary mechanism of FAAH inhibition.…”

“…Kinetic studies with Lineweaver-Burk analysis indicated non-competitive FAAH inhibition consistent with acylation covalent modification of the enzyme, and the compounds also did not exhibit time-dependent inhibition of FAAH. 41,42 …”

Chemical Probes of Endocannabinoid Metabolism

“…Oxime and enol carbamates. Oxime carbamates have been reported as reversible FAAH inhibitors in the patent (Sit et al, 2003) and academic (Gattinoni et al, 2010b;Sit et al, 2010) literature. One member of this class, BMS-469908 (Fig.…”

Biphenyl-3-yl alkylcarbamates as fatty acid amide hydrolase (FAAH) inhibitors: Steric effects of N-alkyl chain on rat plasma and liver stability

“…The ability of selective FAAH inhibitors to upregulate anandamide signaling at cannabinoid receptors, thus causing a variety of potentially favorable effects in animal models, has fueled the discovery of various chemical scaffolds that result in FAAH inhibition [13,14,15,16,17]. Our work has focused on cyclohexylcarbamic acid biphenyl-3-yl esters [18,19] and has led to several interesting molecules such as URB597 [18,20,21], URB694 [22,23,24] and URB937 [25] (See Figure 1).…”