PF-04457845

PF-04457845

Clinical data
ATC code	None
Legal status
Legal status	Investigational New Drug
Identifiers
IUPAC name N-pyridazin-3-yl-4-[(3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl)methylidene]piperidine-1-carboxamide
PubChem (CID)	24771824
ChemSpider	26390839
UNII	H4C81M8YYW
ChEMBL	CHEMBL1651534
Chemical and physical data
Formula	C23H20F3N5O2
Molar mass	455.432 g/mol
3D model (Jmol)	Interactive image
SMILES n4ncccc4NC(=O)N(CC3)CC\C3=C/c2cc(ccc2)Oc(cc1)ncc1C(F)(F)F
InChI InChI=1S/C23H20F3N5O2/c24-23(25,26)18-6-7-21(27-15-18)33-19-4-1-3-17(14-19)13-16-8-11-31(12-9-16)22(32)29-20-5-2-10-28-30-20/h1-7,10,13-15H,8-9,11-12H2,(H,29,30,32) Key:BATCTBJIJJEPHM-UHFFFAOYSA-N

PF-04457845 is a potent and exquisitely selective inhibitor of the enzyme fatty acid amide hydrolase (FAAH), with an IC₅₀ of 7.2nM, and both analgesic and antiinflammatory effects in animal studies comparable to naproxen.^[1]

It has been well tolerated in human trials even at high dose ranges with no evidence for cognitive dysfunction, and has completed Phase II clinical trials for the treatment of osteoarthritis,^[1][2][3][4] but was found to be ineffective.^[5]

See also

• FAAH inhibitor
  • 4-Nonylphenylboronic acid
  • LY-2183240
  • URB-597
  • BIA 10-2474, problems in phase 1

References

1. Johnson, D. S.; Stiff, C.; Lazerwith, S. E.; Kesten, S. R.; Fay, L. K.; Morris, M.; Beidler, D.; Liimatta, M. B.; Smith, S. E.; Dudley, D. T.; Sadagopan, N.; Bhattachar, S. N.; Kesten, S. J.; Nomanbhoy, T. K.; Cravatt, B. F.; Ahn, K. (2011). "Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor". ACS Medicinal Chemistry Letters. 2 (2): 91–96. doi:10.1021/ml100190t. PMC 3109749. PMID 21666860.
2. Ahn K, Smith SE, Liimatta MB, Beidler D, Sadagopan N, Dudley DT, Young T, Wren P, Zhang Y, Swaney S, Van Becelaere K, Blankman JL, Nomura DK, Bhattachar SN, Stiff C, Nomanbhoy TK, Weerapana E, Johnson DS, Cravatt BF. Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain. Journal of Pharmacology and Experimental Therapeutics. 2011 Jul;338(1):114-24. PMID 21505060
3. Li, G. L.; Winter, H.; Arends, R.; Jay, G. W.; Le, V.; Young, T.; Huggins, J. P. (2012). "Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects". British Journal of Clinical Pharmacology. 73 (5): 706–716. doi:10.1111/j.1365-2125.2011.04137.x. PMID 22044402.
4. A Study To Investigate Whether PF-04457845 Is Effective In Treating Pain, Is Safe And Tolerable In Patients With Osteoarthritis Of The Knee
5. Huggins, J. P.; Smart, T. S.; Langman, S.; Taylor, L.; Young, T. (2012). "An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee". Pain. 153 (9): 1837. doi:10.1016/j.pain.2012.04.020.