IC50: 14 nM for the human recombinant enzyme

JP83 is an irreversible fatty acyl amide hydrolase (FAAH) inhibitor.

The enzyme fatty acyl amide hydrolase (FAAH) is capable of hydrolyzing anandamide and other esters and amides with long unsaturated acyl chains, which is widely expressed in brain and other tissues.

In vitro: JP83 was identified as an irreversible FAAH inhibitor of the carbamate class when it was tested using radiolabeled oleamide as the substrate. MS results indicated that it inhibited FAAH by carbamylation of the enzyme’s serine nucleophile. In addition, JP83 was found to be able to inhibit FAAH with equal or greater potency than URB597 [1].

In vivo: Mice were treated with JP104, a close analog of JP83, after which they were sacrificed and their tissues removed for click chemistry analysis. It was found that at 1 mg/kg of JP104, FAAH labeling was ~80% of maximum in the brain, while none of the liver and kidney targets were modified to greater than 20%. Furthermore, the nearly complete inactivation of brain FAAH by JP104 at 1 mg/kg was confirmed by competitive ABPP studies with FP-Rh. In contrast, JP104 couldnot reduce the intensity of FP-Rh signals in liver and kidney proteomes significantly [1].

Clinical trial: So far, no clinical study has been conducted.

Reference:
[1] Alexander, J. P., and Cravatt, B.F. Mechanism of carbmate inactivation of FAAH: Implications for the design of covalent inhibitors and in vivo functional probes for enzymes. Chemistry & Biology 12, 1179-1187 (2005).