Anticancer Potential of Small-Molecule Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase.

Recently fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors have been in the limelight due to their anticancer potential. Both FAAH and MAGL are the endocannabinoid degrading enzymes that hydrolyze several endogenous ligands, mainly anandamide (AEA) and 2-arachidonic glycerol (2-AG), which regulate various pathophysiological conditions in the body such as emotion, cognition, energy balance, pain sensation, neuroinflammation, and cancer cell proliferation. FAAH and MAGL inhibitors block the metabolism of AEA and 2-AG, increase endogenous levels of fatty acid amides, and exert various therapeutic effects including chronic pain, metabolic disorders, psychoses, nausea and vomiting, depression, and anxiety disorders. FAAH and MAGL are primarily neurotherapeutic targets, but their contribution to various types of carcinomas are significant. Inhibitors of these enzymes either alone or as multitarget agents, or with supra-additive effects show the potential effect in ovarian, breast, prostate, and colorectal cancers. Besides highlighting the role of FAAH and MAGL in cancer progression, this review provides an update on the anticancer capabilities of known and newly discovered FAAH and MAGL inhibitors and also provides further directions to develop FAAH and MAGL inhibitors as new candidates for cancer therapy.

Jaiswal S ，Ayyannan SR 《-》

Piperazine and piperidine carboxamides and carbamates as inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

The key hydrolytic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), are potential targets for various therapeutic applications. In this paper, we present more extensively the results of our previous work on piperazine and piperidine carboxamides and carbamates as FAAH and MAGL inhibitors. The best compounds of these series function as potent and selective MAGL/FAAH inhibitors or as dual FAAH/MAGL inhibitors at nanomolar concentrations. This study revealed that MAGL inhibitors should comprise leaving-groups with a conjugate acid pKa of 8-10, while diverse leaving groups are tolerated for FAAH inhibitors.

Korhonen J ，Kuusisto A ，van Bruchem J ，Patel JZ ，Laitinen T ，Navia-Paldanius D ，Laitinen JT ，Savinainen JR ，Parkkari T ，Nevalainen TJ ... -  《-》

Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB(1) receptor-mediated discriminative stimulus in mice.

Substantial challenges exist for investigating the cannabinoid receptor type 1 (CB1)-mediated discriminative stimulus effects of the endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), compared with exogenous CB1 receptor agonists, such as Δ9-tetrahydrocannabinol (THC) and the synthetic cannabinoid CP55,940. Specifically, each endocannabinoid is rapidly degraded by the respective hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Whereas MAGL inhibitors partially substitute for THC and fully substitute for CP55,940, FAAH inhibitors do not substitute for either drug. Interestingly, combined FAAH-MAGL inhibition results in full THC substitution, and the dual FAAH-MAGL inhibitor SA-57 serves as its own discriminative training stimulus. Because MAGL inhibitors fully substitute for SA-57, we tested whether the selective MAGL inhibitor MJN110 would serve as a training stimulus. Twelve of 13 C57BL/6J mice learned to discriminate MJN110 from vehicle, and the CB1 receptor antagonist rimonabant dose-dependently blocked its discriminative stimulus. CP55,940, SA-57, and another MAGL inhibitor JZL184, fully substituted for MJN110. In contrast, the FAAH inhibitor PF-3845 failed to substitute for the MJN110 discriminative stimulus, but produced a 1.6 (1.1-2.2; 95% confidence interval) leftward shift in the MJN110 dose-response curve. Inhibitors of other relevant enzymes (i.e., ABHD6, COX-2) and nicotine did not engender substitution. Diazepam partially substituted for MJN110, but rimonabant failed to block this partial effect. These findings suggest that MAGL normally throttles 2-AG stimulation of CB1 receptors to a magnitude insufficient to produce cannabimimetic subjective effects. Accordingly, inhibitors of this enzyme may release this endogenous brake producing effects akin to those produced by exogenously administered cannabinoids.

Owens RA ，Mustafa MA ，Ignatowska-Jankowska BM ，Damaj MI ，Beardsley PM ，Wiley JL ，Niphakis MJ ，Cravatt BF ，Lichtman AH ... -  《-》

(4-Phenoxyphenyl)tetrazolecarboxamides and related compounds as dual inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

Inhibitors of the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principle enzymes involved in the degradation of endogenous cannabinoids like anandamide and 2-arachidonoylglycerol, have potential utility in the treatment of several disorders including pain, inflammation and anxiety. In the present study, the effectivity and selectivity of eight known FAAH and MAGL inhibitors for inhibition of the appropriate enzyme were measured applying in vitro assays, which work under comparable conditions. Because many of the known FAAH and MAGL inhibitors simply consist of a lipophilic scaffold to which a heterocyclic system is bound, furthermore, different heterocyclic structures were evaluated for their contribution to enzyme inhibition by attaching them to the same lipophilic backbone, namely 4-phenoxybenzene. One of the most active compound synthesized during this investigation was N,N-dimethyl-5-(4-phenoxyphenyl)-2H-tetrazole-2-carboxamide (16) (IC50 FAAH: 0.012 μM; IC50 MAGL: 0.028 μM). This inhibitor was systematically modified in the lipophilic 4-phenoxyphenyl region. Structure-activity relationship studies revealed that the inhibitory potency against FAAH and MAGL, respectively, could still be increased by replacement of the phenoxy residue of 16 by 3-chlorophenoxy (45) or pyrrol-1-yl groups (49). Finally, the tetrazolecarboxamide 16 and some related compounds were tested for metabolic stability with rat liver S9 fractions showing that these kind of FAAH/MAGL inhibitors are readily inactivated by cleavage of the bond between the tetrazole ring and its carboxamide substituent.

Holtfrerich A ，Hanekamp W ，Lehr M 《-》

A comparison of novel, selective fatty acid amide hydrolase (FAAH), monoacyglycerol lipase (MAGL) or dual FAAH/MAGL inhibitors to suppress acute and anticipatory nausea in rat models.

Parker LA ，Limebeer CL ，Rock EM ，Sticht MA ，Ward J ，Turvey G ，Benchama O ，Rajarshi G ，Wood JT ，Alapafuja SO ，Makriyannis A ... -  《-》