Fatty acid amide hydrolase FAAH inhibitors

A competitive version of ABPP identifies the target(s) and assesses the selectivity of an enzyme inhibitor in biological systems by gauging how well the inhibitor slows the enzyme s reaction with an ABP. For example, fluorophosphonate ABP 3 was used to profile the selectivity of fatty acid amide hydrolase (FAAH) inhibitors within the serine hydrolase superfamily [27] (FAAH hydrolyzes endocannabinoids such as anandamide). Serine hydrolases that exhibited reduced labeling by the probe in the presence of inhibitor were scored as targets of the inhibitor. Urea FAAH inhibitors exemplified by PF-3845 (5) that covalently modify the active-site serine nucleophile of FAAH were found to be exquisitely selective for FAAH in brain and liver... 

Similarly, MyllymSki et al. have employed this concept in the synthesis of aryl ketones via the reaction of the lithio benzothiazole with an aryl acid chloride to produce the desired ketone. A series of such carbonyl compounds was synthesized and evaluated as potential fatty acid amide hydrolase (FAAH) inhibitors. 

A series of thiadiazolopiperazinyl aryl urea fatty acid amide hydrolase (FAAH) inhibitors is described. The molecules were found to inhibit the enzyme by acting as slowly turned over substrates, likely forming a transient covalent bond with Ser241. SAR and PK properties are presented. 

Anandamide is rapidly hydrolysed enzymatically to arachidonic acid and ethanol-amine by a fatty acid amide hydrolase (FAAH) [50], The molecular characterization, cloning and expression of FAAH have been reported in a recent study [51]. FAAH can be blocked with either the general serine protease inhibitor phenyl methy(sulphonyl fluoride [38] or with the highly efficient methyl arachidonyl fluorophsphonate [52], The non-steroidal antiinflammatory ibuprofen in therapeutic doses, but not aspirin, sulindac or acetaminophen, also inhibits anandamide metabolism [53], This observation may have therapeutic implications. 

Inhibitors of Fatty Acid Amide Hydrolase (FAAH) Most Often Used In Vivo... 

Lodola, A., Mor, M., Rivara, S., Christov, C., Tarzia, G., Piomelli, D., MulhoUand, A.J. Identification of productive inhibitor binding orientation in fatty acid amide hydrolase (FAAH) by QM/MM mechanistic modelling. Ghem. Gommun. 2008(2), 214-6. 

Min X, Thibault ST, Porter AC, Gustin DJ, Carlson TJ, Xu H, Lindstrom M, Xu G, Uyeda C, Ma Z, Li Y, Kayser F, Walker NPC, Wang Z (2011) Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH). Proc Natl Acad Sci USA 108 7379... 

The same group demonstrated the applicability of this strategy in the efficient seven-step synthesis of an amide-ftmctionaUzed monothiohydantoin 34, a novel inhibitor of fatty acid amide hydrolase (FAAH) (ICjg=23.4 1.1 pM) (Scheme 10.10) [33], which is a membrane-bound enzyme. 

Figure 6. Inhibitors of fatty acid amide hydrolase (FAAH).

Compound 104 was shown to be a potent, selective, and reversible non-covalent FAAH (fatty acid amide hydrolase) inhibitor for the treatment of inflammatory and neuropathic pain. With respect to other inhibitors proposed before, the peculiarities that make it so effective and promising are the reversible binding with the FAAH and the replacement of the classical and weU-assessed pyrazole ring with an oxazole ring (14AMCL717). 

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