A novel inhibitor of fatty acid amide hydrolase, the enzyme responsible for the hydrolysis of the endocannabinoid anandamide

Abstract

Inhibitors of fatty acid amide hydrolase (FAAH) have shown utility in models of inflammatory pain, and in some cases in models of neuropathic pain. The non‐steroidal anti‐inflammatory drug ibuprofen is a weak inhibitor of FAAH (IC50 value ~200 µM, Fowler et al., J Pharmacol Exp Ther 283 [1997] 729‐34), but can be used as a template for the design of more potent compounds. In this respect we have reported an analogue of ibuprofen, ibu‐am5, that retains the COX inhibitory properties of ibuprofen, but is a more potent FAAH inhibitor (IC50 value 5 µM, Holt et al., Eur J Pharmacol 565 [2007] 26‐36). Here we have investigated a series of 28 analogues of acetaminophen, ibuprofen and flufenamic acid for their FAAH inhibitory properties. The most potent compound, TPE22 (4‐acetamidophenyl 2‐(4‐(2‐(trifluoromethyl)pyridin‐4‐ylamino)phenyl)propanoate) inhibited rat brain FAAH in the submicromolar range. The inhibition, which was of mixed type, with Ki(slope) and Ki(intercept) values of 160 nM and 1.9 µM, respectively, was not increased upon preincubation of the compound with FAAH. Thus, TPE22 is a potent novel inhibitor of FAAH.