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Befiradol

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Befiradol
Clinical data
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Identifiers
  • 3-Chloro-4-fluorophenyl-[4-fluoro-4-([(5-methylpyridin-2-yl)methylamino]methyl)piperidin-1-yl]methanone
CAS Number
PubChemCID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard(EPA)
Chemical and physical data
FormulaC20H22ClF2N3O
Molar mass393.86g·mol−1
3D model (JSmol)
  • Cc1ccc(nc1)CNCC2(CCN(CC2)C(=O)c3ccc(c(c3)Cl)F)F
  • InChI=1S/C20H22ClF2N3O/c1-14-2-4-16(25-11-14)12-24-13-20(23)6-8-26(9-7-20)19(27)15-3-5-18(22)17(21)10-15/h2-5,10-11,24H,6-9,12-13H2,1H3checkY
  • Key:PKZXLMVXBZICTF-UHFFFAOYSA-NcheckY
☒NcheckY(what is this?)(verify)

Befiradol(F-13,640;NLX-112) is an experimental drug being studied for the treatment oflevodopa-induced dyskinesia.It is apotentandselective5-HT1Areceptorfull agonist.

Pharmacology

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In recombinant cell lines expressing human5-HT1A receptors,befiradol exhibits high agonist efficacy for a variety of signal transduction read-outs, includingERKphosphorylation,G-proteinactivation,receptor internalizationandadenylyl cyclaseinhibition.[1]In rat hippocampal membranes it preferentially activatesGalphaO proteins.[1]In neurochemical experiments, befiradol activated 5-HT1A autoreceptors in rat dorsal Raphe nucleus as well as 5-HT1A heteroreceptors on pyramidal neurons in the frontal cortex.[2]In rat models, it has powerfulanalgesicandantiallodyniceffects comparable to those of high doses ofopioidpainkillers,but with fewer and less prominentside effects,as well as little or no development oftolerancewith repeated use.[3][4][5][6][7]

Astructure–activity relationship(SAR) study revealed that replacement of the dihalophenyl moiety by 3-benzothienylincreases maximalefficacyfrom 84% to 124% (Ki=2.7 nM).[8][9]

History

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Befiradol was discovered and developed byPierre Fabre Médicament,a French pharmaceuticals company who initially developed it as a treatment for chronic pain. In September 2013, befiradol was out-licensed toNeurolixis,a US-based biotechnology company. Neurolixis announced that it intended to re-purpose befiradol for the treatment oflevodopa-induced dyskinesiainParkinson's disease.[10]In support of this indication, Neurolixis received several research grants[11]from theMichael J. Fox Foundationand preclinical data was published describing the activity of befiradol inanimal models of Parkinson's disease.[12][13]Studies published in 2020 using non-human primate models of Parkinson's disease, (MPTP-treated marmosets andMPTP-treated macaques), found that befiradol potently reducedLevodopa-induced dyskinesiaat oral doses as low as 0.1 to 0.4 mg/kg.[14][15]In January 2018, the British charityParkinson's UKannounced that it had awarded Neurolixis a grant to advance development of befiradol up to clinical phase in Parkinson's disease patients.[16]

Clinical Ph2A Trial for dyskinesia in Parkinson's disease

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In March 2019, Neurolixis announced that the USFood and Drug Administration(FDA) gave a positive response to Neurolixis'Investigational New Drug(IND) application for NLX-112 to be tested in a Phase 2 clinical study in Parkinson's disease patients with troublesomelevodopa-induced dyskinesia.[17] On 22 November 2020,The Sunday Timesreported that the two charities,Parkinson's UKandMichael J. Fox Foundation,were jointly investing $2 million to support a clinical trial on befiradol in Parkinson's disease patients with troublesomeLevodopa-induced dyskinesia,a potentially "life changing" drug.[18]On 23 November 2020,Parkinson's UKandMichael J. Fox Foundation,confirmed their funding in an official announcement.[19]Neurolixisannounced on 30 November 2021 the start ofpatient recruitmentin the clinical trial. The trial is listed on the U.S. National Library of Medicine clinical trials register.[20]On 20 March 2023, a joint press release fromNeurolixis,Parkinson's UKandMichael J. Fox Foundationannounced that the clinical trial had met its primary endpoint of safety and tolerability, and also the secondary endpoint of efficacy in reducingLevodopa-induced dyskinesiain the patients.[21]Moreover, a later announcement (7 July 2023) disclosed that the clinical trial had also found that befiradol reducedparkinsonismsymptoms (such as slowness of movement, tremor and rigidity), as well asLevodopa-induced dyskinesia,raising the prospect of developing a "dual-efficacy therapy" forParkinson's disease.[22]

18F-Befiradol as an agonist PET radiotracer for brain imaging

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As well as studies on befiradol for treatment of movement disorders, other researchers have investigated it as a novel radiotracer for brain imaging studies bypositron emission tomography.Thus befiradol labeled with [18F] (also known as 18F-F13640) has been used to study the distribution of serotonin5-HT1A receptorsin rat, cat, macaque and human. Because befiradol is anagonist,it enables the detection of 5-HT1A receptors which are specifically in a functionally active state, whereasantagonistradiotracers label the total receptor population.[23][24]

See also

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References

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  1. ^abNewman-Tancredi A, Martel JC, Cosi C, Heusler P, Lestienne F, Varney MA, et al. (September 2017). "Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1Areceptor agonist ".The Journal of Pharmacy and Pharmacology.69(9): 1178–1190.doi:10.1111/jphp.12762.PMID28612503.S2CID13676820.
  2. ^Lladó-Pelfort L, Assié MB, Newman-Tancredi A, Artigas F, Celada P (May 2012). "In vivo electrophysiological and neurochemical effects of the selective 5-HT1A receptor agonist, F13640, at pre- and postsynaptic 5-HT1A receptors in the rat".Psychopharmacology.221(2): 261–272.doi:10.1007/s00213-011-2569-9.PMID22147258.S2CID18779324.
  3. ^Bardin L, Tarayre JP, Malfetes N, Koek W, Colpaert FC (April 2003). "Profound, non-opioid analgesia produced by the high-efficacy 5-HT(1A) agonist F 13640 in the formalin model of tonic nociceptive pain".Pharmacology.67(4): 182–194.doi:10.1159/000068404.PMID12595749.S2CID25882138.
  4. ^Bruins Slot LA, Koek W, Tarayre JP, Colpaert FC (April 2003). "Tolerance and inverse tolerance to the hyperalgesic and analgesic actions, respectively, of the novel analgesic, F 13640".European Journal of Pharmacology.466(3): 271–279.doi:10.1016/S0014-2999(03)01566-8.PMID12694810.
  5. ^Bardin L, Assié MB, Pélissou M, Royer-Urios I, Newman-Tancredi A, Ribet JP, et al. (March 2005). "Dual, hyperalgesic, and analgesic effects of the high-efficacy 5-hydroxytryptamine 1A (5-HT1A) agonist F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt]: relationship with 5-HT1A receptor occupancy and kinetic parameters".The Journal of Pharmacology and Experimental Therapeutics.312(3): 1034–1042.doi:10.1124/jpet.104.077669.PMID15528450.S2CID42446435.
  6. ^Colpaert FC, Deseure K, Stinus L, Adriaensen H (February 2006). "High-efficacy 5-hydroxytryptamine 1A receptor activation counteracts opioid hyperallodynia and affective conditioning".The Journal of Pharmacology and Experimental Therapeutics.316(2): 892–899.doi:10.1124/jpet.105.095109.PMID16254131.S2CID8820667.
  7. ^Deseure K, Bréand S, Colpaert FC (July 2007). "Curative-like analgesia in a neuropathic pain model: parametric analysis of the dose and the duration of treatment with a high-efficacy 5-HT(1A) receptor agonist".European Journal of Pharmacology.568(1–3): 134–141.doi:10.1016/j.ejphar.2007.04.022.PMID17512927.
  8. ^Bollinger S, Hübner H, Heinemann FW, Meyer K, Gmeiner P (October 2010). "Novel pyridylmethylamines as highly selective 5-HT(1A) superagonists".Journal of Medicinal Chemistry.53(19): 7167–7179.doi:10.1021/jm100835q.PMID20860381.
  9. ^Vacher B, Bonnaud B, Funes P, Jubault N, Koek W, Assié MB, et al. (May 1999). "Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors".Journal of Medicinal Chemistry.42(9): 1648–1660.CiteSeerX10.1.1.325.8872.doi:10.1021/jm9806906.PMID10229633.
  10. ^"Neurolixis Announces In-Licensing of Two Clinical Compounds From Pierre Fabre Medicament"(PDF).Neurolixis, Inc. 23 September 2013.
  11. ^"Parkinson's Disease Grants funded by the Michael J. Fox Foundation | Parkinson's Disease".The Michael J. Fox Foundation for Parkinson's Research | Parkinson's Disease.Retrieved2017-06-23.
  12. ^Iderberg H, McCreary AC, Varney MA, Kleven MS, Koek W, Bardin L, et al. (September 2015). "NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat".Experimental Neurology.271:335–350.doi:10.1016/j.expneurol.2015.05.021.PMID26037043.S2CID35525495.
  13. ^McCreary AC, Varney MA, Newman-Tancredi A (June 2016). "The novel 5-HT1A receptor agonist, NLX-112 reduces l-DOPA-induced abnormal involuntary movements in rat: A chronic administration study with microdialysis measurements".Neuropharmacology.105:651–660.doi:10.1016/j.neuropharm.2016.01.013.PMID26777281.S2CID1979117.
  14. ^Depoortere R, Johnston TH, Fox SH, Brotchie JM, Newman-Tancredi A (September 2020). "The selective 5-HT1Areceptor agonist, NLX-112, exerts anti-dyskinetic effects in MPTP-treated macaques ".Parkinsonism & Related Disorders.78:151–157.doi:10.1016/j.parkreldis.2020.08.009.PMID32846366.S2CID221343904.
  15. ^Fisher R, Hikima A, Morris R, Jackson MJ, Rose S, Varney MA, et al. (May 2020)."The selective 5-HT1Areceptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets ".Neuropharmacology.167:107997.doi:10.1016/j.neuropharm.2020.107997.PMC7103782.PMID32057799.
  16. ^"Investing in a new treatment for dyskinesia".Parkinson's UK. 24 January 2018.
  17. ^"FDA Approves Neurolixis IND Application for a Clinical Trial with NLX-112 in Parkinson's Disease".Neurolixis, Inc. 12 March 2019 – via PRLog.
  18. ^Gregory A (22 November 2020)."'Life-changing' drug to calm Parkinson's twitches set for human trials ".Thetimes.co.uk.
  19. ^"Global charities join forces to drive forward new drug for Parkinson's".The Michael J. Fox Foundation for Parkinson's Research(Press release) – via Cision US Inc.
  20. ^Clinical trial numberNCT05148884for "Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in L-dopa-induced Dyskinesia" atClinicalTrials.gov
  21. ^"Neurolixis Announces Positive Ph2A Proof-of-Concept on NLX-112 in Levodopa-Induced Dyskinesia in Parkinson's Disease".20 March 2023 – via Newsmatics Inc.
  22. ^Massey N (7 July 2023)."Researchers hopeful of treatment of Parkinson's by 2030 with 'dual efficacy' drug".The Independent.Retrieved26 July2023.
  23. ^Colom M, Vidal B, Fieux S, Redoute J, Costes N, Lavenne F, et al. (2021)."[18F]F13640, a 5-HT1AReceptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations ".Frontiers in Neuroscience.15:622423.doi:10.3389/fnins.2021.622423.PMC7982540.PMID33762906.
  24. ^Courault P, Lancelot S, Costes N, Colom M, Le Bars D, Redoute J, et al. (May 2023)."[18F]F13640: a selective agonist PET radiopharmaceutical for imaging functional 5-HT1Areceptors in humans ".European Journal of Nuclear Medicine and Molecular Imaging.50(6): 1651–1664.doi:10.1007/s00259-022-06103-1.PMC10119077.PMID36656363.
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