PF-04457845
Clinical data
ATC code
  • None
Legal status
Legal status
Identifiers
  • N-pyridazin-3-yl-4-[(3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl)methylidene]piperidine-1-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H20F3N5O2
Molar mass455.441 g·mol−1
3D model (JSmol)
  • n4ncccc4NC(=O)N(CC3)CC\C3=C/c2cc(ccc2)Oc(cc1)ncc1C(F)(F)F
  • 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]

As of 2021, several studies have shown that this novel FAAH inhibitor may reduce cannabis withdrawal symptoms and cannabis use in men, and might represent an effective and safe approach for the treatment of cannabis use disorder.[6][7][8]

See also

References

  1. ^ a b Johnson DS, Stiff C, Lazerwith SE, Kesten SR, Fay LK, Morris M, et al. (February 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, et al. (July 2011). "Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain". The Journal of Pharmacology and Experimental Therapeutics. 338 (1): 114–24. doi:10.1124/jpet.111.180257. PMC 3126636. PMID 21505060.
  3. ^ Li GL, Winter H, Arends R, Jay GW, Le V, Young T, Huggins JP (May 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): 706–16. doi:10.1111/j.1365-2125.2011.04137.x. PMC 3403198. PMID 22044402.
  4. ^ Clinical trial number NCT00981357 for "A Study To Investigate Whether PF-04457845 Is Effective In Treating Pain, Is Safe And Tolerable In Patients With Osteoarthritis Of The Knee" at ClinicalTrials.gov
  5. ^ Huggins JP, Smart TS, Langman S, Taylor L, Young T (September 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): 1837–46. doi:10.1016/j.pain.2012.04.020. PMID 22727500. S2CID 25179328.
  6. ^ "Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial". The Lancet. 6 (1): 35–45. 2019-01-01. doi:10.1016/S2215-0366(18)30427-9. ISSN 2215-0366.
  7. ^ Bonifacio, Maria Joao; Sousa, Filipa; Aires, Catia; Loureiro, Ana I.; Fernandes-Lopes, Carlos; Palma, Nuno; Moser, Paul; Soares-da-Silva, Patricio (2018). "Evaluation of the Potency and Selectivity of the Novel Faah Inhibitor Bia 10-2474 in Comparison with Pf-04457845 and Jnj-42165279". The FASEB Journal. 32 (S1): 692.14–692.14. doi:10.1096/fasebj.2018.32.1_supplement.692.14. ISSN 1530-6860.
  8. ^ Nielsen, Suzanne; Sabioni, Pamela; Gowing, Linda; Le Foll, Bernard (2020), Nader, Michael A.; Hurd, Yasmin L. (eds.), "Pharmacotherapies for Cannabis Use Disorders: Clinical Challenges and Promising Therapeutic Agents", Substance Use Disorders: From Etiology to Treatment, Handbook of Experimental Pharmacology, Cham: Springer International Publishing, pp. 355–372, doi:10.1007/164_2019_258, ISBN 978-3-030-33679-0, retrieved 2021-08-22