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. 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, but was found to be ineffective.
Chemical Formula: C23H20F3N5O2
Exact Mass: 455.15691
Molecular Weight: 455.44121
Elemental Analysis: C, 60.66; H, 4.43; F, 12.51; N, 15.38; O, 7.03
InChi Code: 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)
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life:>2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
PF-04457845 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH with high in vitro potency (kinact/Ki and IC50 values of 40300 M-1s-1 and 7.2 nM, respectively, for human FAAH). PF-04457845 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. PF-04457845 completely inhibits FAAH in human and mouse membrane proteomes at both 10 and 100 μM with no off targets. PF-04457845 is completely selective for FAAH, and none of the other FP-reactive serine hydrolases in the tested tissues are inhibited by PF-04457845 even at 100 μM.
Oral administration of PF-04457845 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Oral administration of PF-04457845 causes a significant inhibition of mechanical allodynia measured after 4 h with a minimum effective dose (MED) of 0.1 mg/kg. Furthermore, at 0.1 mg/kg (p.o.), PF-04457845 inhibits the pain response to a comparable degree as the nonsteroidal anti-inflammatory drug naproxen at 10 mg/kg. FAAH is confirmed to be completely inhibited in mice treated with PF-04457845 at 1 and 10 mg/kg p.o. by competitive activity-based protein profiling (ABPP) study.
Lodola A, Castelli R, Mor M, Rivara S. Fatty acid amide hydrolase inhibitors: a patent review (2009 - 2014). Expert Opin Ther Pat. 2015 Nov;25(11):1247-66. doi: 10.1517/13543776.2015.1067683. Epub 2015 Sep 28. PubMed PMID: 26413912.
Boileau I, Rusjan PM, Williams B, Mansouri E, Mizrahi R, De Luca V, Johnson DS, Wilson AA, Houle S, Kish SJ, Tong J. Blocking of fatty acid amide hydrolase activity with PF-04457845 in human brain: a positron emission tomography study with the novel radioligand [(11)C]CURB. J Cereb Blood Flow Metab. 2015 Nov;35(11):1827-35. doi: 10.1038/jcbfm.2015.133. Epub 2015 Jun 17. PubMed PMID: 26082009.
Bryden LA, Nicholson JR, Doods H, Pekcec A. Deficits in spontaneous burrowing behavior in the rat bilateral monosodium iodoacetate model of osteoarthritis: an objective measure of pain-related behavior and analgesic efficacy. Osteoarthritis Cartilage. 2015 Sep;23(9):1605-12. doi: 10.1016/j.joca.2015.05.001. Epub 2015 May 9. PubMed PMID: 25966657.
Benson N, Metelkin E, Demin O, Li GL, Nichols D, van der Graaf PH. A systems pharmacology perspective on the clinical development of Fatty Acid amide hydrolase inhibitors for pain. CPT Pharmacometrics Syst Pharmacol. 2014 Jan 15;3:e91. doi: 10.1038/psp.2013.72. PubMed PMID: 24429592; PubMed Central PMCID: PMC3910012.
Hicks JW, Parkes J, Sadovski O, Tong J, Houle S, Vasdev N, Wilson AA. Synthesis and preclinical evaluation of [11C-carbonyl]PF-04457845 for neuroimaging of fatty acid amide hydrolase. Nucl Med Biol. 2013 Aug;40(6):740-6. doi: 10.1016/j.nucmedbio.2013.04.008. Epub 2013 May 31. PubMed PMID: 23731552; PubMed Central PMCID: PMC3737387.
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