Befiradol

Befiradol (F-13,640; NLX-112) is an experimental drug being studied for the treatment of levodopa-induced dyskinesia. It is a potent and selective 5-HT1A receptor full agonist.

Befiradol
Clinical data
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Identifiers
IUPAC name
  • 3-Chloro-4-fluorophenyl-[4-fluoro-4-([(5-methylpyridin-2-yl)methylamino]methyl)piperidin-1-yl]methanone
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H22ClF2N3O
Molar mass393.86 g·mol−1
3D model (JSmol)
SMILES
  • Cc1ccc(nc1)CNCC2(CCN(CC2)C(=O)c3ccc(c(c3)Cl)F)F
InChI
  • 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,6-9,12-13H2,1H3 Y
  • Key:PKZXLMVXBZICTF-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Pharmacology

In recombinant cell lines expressing human 5-HT1A receptors, befiradol exhibits high agonist efficacy for a variety of signal transduction read-outs, including ERK phosphorylation, G-protein activation, receptor internalization and adenylyl cyclase inhibition.[1] In rat hippocampal membranes it preferentially activates GalphaO 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] It has powerful analgesic and antiallodynic effects comparable to those of high doses of opioid painkillers, but with fewer and less prominent side effects, as well as little or no development of tolerance with repeated use.[3][4][5][6][7]

A structure–activity relationship (SAR) study revealed that replacement of the dihalophenyl moiety by 3-benzothienyl increases maximal efficacy from 84% to 124% (Ki=2.7 nM).[8][9]

History

Befiradol was discovered and developed by Pierre Fabre Médicament, a French pharmaceuticals company. In September 2013, befiradol was out-licensed to Neurolixis, a California-based biotechnology company. Neurolixis announced that it intends to re-purpose befiradol for the treatment of levodopa-induced dyskinesia in Parkinson's disease.[10] In support of this indication, Neurolixis received several research grants[11] from the Michael J. Fox Foundation and preclinical data was published describing the activity of befiradol in animal models of Parkinson's disease.[12][13] In January 2018, the British charity Parkinson's UK announced that it had awarded Neurolixis a grant to advance development of befiradol up to clinical phase in Parkinson's disease patients.[14] In March 2019, Neurolixis announced that the US Food 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 troublesome levodopa-induced dyskinesia.[15] Studies published in 2020 using non-human primate models of Parkinson's disease, (MPTP-treated marmosets and MPTP-treated macaques), found that befiradol potently reduced Levodopa-induced dyskinesia at oral doses as low as 0.1 to 0.4 mg/kg.[16][17] On 22 November 2020, The Sunday Times reported that the two charities, Parkinson's UK and Michael J. Fox Foundation, were jointly investing $2 million to support a clinical trial on befiradol in Parkinson's disease patients with troublesome Levodopa-induced dyskinesia, a potentially "life changing" drug.[18] On 23 November 2020, Parkinson's UK and Michael J. Fox Foundation, confirmed their funding in an official announcement.[19] Neurolixis announced on 30 November 2021 the start of patient recruitment in the clinical trial.[20] The trial is listed on the U.S. National Library of Medicine clinical trials register.[21]

See also

References
  1. Newman-Tancredi A, Martel JC, Cosi C, Heusler P, Lestienne F, Varney MA, Cussac D (September 2017). "Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist". The Journal of Pharmacy and Pharmacology. 69 (9): 1178–1190. doi:10.1111/jphp.12762. PMID 28612503. S2CID 13676820.
  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. PMID 22147258. S2CID 18779324.
  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. PMID 12595749. S2CID 25882138.
  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. PMID 12694810.
  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. PMID 15528450. S2CID 42446435.
  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. PMID 16254131. S2CID 8820667.
  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. PMID 17512927.
  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. PMID 20860381.
  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. CiteSeerX 10.1.1.325.8872. doi:10.1021/jm9806906. PMID 10229633.
  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. Retrieved 2017-06-23.
  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. PMID 26037043. S2CID 35525495.
  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. PMID 26777281. S2CID 1979117.
  14. "Investing in a new treatment for dyskinesia". Parkinson's UK. 24 January 2018.
  15. "FDA Approves Neurolixis IND Application for a Clinical Trial with NLX-112 in Parkinson's Disease". Neurolixis, Inc. 12 March 2019 – via PRLog.
  16. Depoortere R, Johnston TH, Fox SH, Brotchie JM, Newman-Tancredi A (September 2020). "The selective 5-HT1A receptor 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. PMID 32846366. S2CID 221343904.
  17. Fisher R, Hikima A, Morris R, Jackson MJ, Rose S, Varney MA, et al. (May 2020). "The selective 5-HT1A receptor 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. PMC 7103782. PMID 32057799.
  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 – via Cision US Inc.
  20. "First Patient Dosed in Phase 2a Trial of NLX-112 for the Treatment of L-DOPA Induced Dyskinesia in Parkinson's Disease". Neurolixis. 30 November 2021 – via EINPresswire.com.
  21. Clinical trial number NCT05148884 for "Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in L-dopa-induced Dyskinesia" at ClinicalTrials.gov
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