PF-04457845

PF-04457845
Clinical data
ATC code	None;
Legal status
Legal status	US: 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;
CompTox Dashboard (EPA)	DTXSID00144539 ;
Chemical and physical data
Formula	C23H20F3N5O2
Molar mass	455.432 g/mol g·mol−1
3D model (JSmol)	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]

References

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.
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 (Jul 2011). "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. 338 (1): 114–24. doi:10.1124/jpet.111.180257. PMC 3126636. PMID 21505060.
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. PMC 3403198. PMID 22044402.
A Study To Investigate Whether PF-04457845 Is Effective In Treating Pain, Is Safe And Tolerable In Patients With Osteoarthritis Of The Knee
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. PMID 22727500.

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[Johnson2011-1] 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 (Jul 2011). "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. 338 (1): 114–24. doi:10.1124/jpet.111.180257. PMC 3126636. 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. PMC 3403198. 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. PMID 22727500.

PF-04457845

See also

References