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PF-3845

PF-3845 is a potent, selective, and irreversible fatty acid amide hydrolase (FAAH) inhibitor with a Ki of 0.23 μM.

Fatty acid amide hydrolase (FAAH) is an enzyme that catalyzes N-acyl ethanolamines (NAEs), including the endocannabinoid arachidonoyl ethanolamide (AEA).  PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system. (source: Chem Biol. 2009 Apr 24;16(4):411-20.)

1: Ramesh D, Ross GR, Schlosburg JE, Owens RA, Abdullah RA, Kinsey SG, Long JZ, Nomura DK, Sim-Selley LJ, Cravatt BF, Akbarali HI, Lichtman AH. Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice. J Pharmacol Exp Ther. 2011 Oct;339(1):173-85. Epub 2011 Jun 30. PubMed PMID: 21719468; PubMed Central PMCID: PMC3186294.

2: Kinsey SG, Nomura DK, O'Neal ST, Long JZ, Mahadevan A, Cravatt BF, Grider JR, Lichtman AH. Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice. J Pharmacol Exp Ther. 2011 Sep;338(3):795-802. Epub 2011 Jun 9. PubMed PMID: 21659471; PubMed Central PMCID: PMC3164340.

3: Booker L, Kinsey SG, Abdullah RA, Blankman JL, Long JZ, Ezzili C, Boger DL, Cravatt BF, Lichtman AH. The FAAH Inhibitor PF-3845 Acts in the Nervous System to Reverse Lipopolysaccharide-induced Tactile Allodynia in Mice. Br J Pharmacol. 2011 Apr 20. doi: 10.1111/j.1476-5381.2011.01445.x. [Epub ahead of print] PubMed PMID: 21506952.

4: Kinsey SG, O'Neal ST, Long JZ, Cravatt BF, Lichtman AH. Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay. Pharmacol Biochem Behav. 2011 Mar;98(1):21-7. Epub 2010 Dec 8. PubMed PMID: 21145341; PubMed Central PMCID: PMC3034086.

5: Long JZ, LaCava M, Jin X, Cravatt BF. An anatomical and temporal portrait of physiological substrates for fatty acid amide hydrolase. J Lipid Res. 2011 Feb;52(2):337-44. Epub 2010 Nov 19. PubMed PMID: 21097653; PubMed Central PMCID: PMC3023554.

6: Kinsey SG, Long JZ, Cravatt BF, Lichtman AH. Fatty acid amide hydrolase and monoacylglycerol lipase inhibitors produce anti-allodynic effects in mice through distinct cannabinoid receptor mechanisms. J Pain. 2010 Dec;11(12):1420-8. Epub 2010 Jun 16. PubMed PMID: 20554481; PubMed Central PMCID: PMC2962430.

7: Mileni M, Kamtekar S, Wood DC, Benson TE, Cravatt BF, Stevens RC. Crystal structure of fatty acid amide hydrolase bound to the carbamate inhibitor URB597: discovery of a deacylating water molecule and insight into enzyme inactivation. J Mol Biol. 2010 Jul 23;400(4):743-54. Epub 2010 May 21. PubMed PMID: 20493882; PubMed Central PMCID: PMC3014312.

8: Ahn K, Johnson DS, Mileni M, Beidler D, Long JZ, McKinney MK, Weerapana E, Sadagopan N, Liimatta M, Smith SE, Lazerwith S, Stiff C, Kamtekar S, Bhattacharya K, Zhang Y, Swaney S, Van Becelaere K, Stevens RC, Cravatt BF. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem Biol. 2009 Apr 24;16(4):411-20. PubMed PMID: 19389627; PubMed Central PMCID: PMC2692831.