:Befiradol

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 461088268

| IUPAC_name = 3-Chloro-4-fluorophenyl-[4-fluoro-4-([(5-methylpyridin-2-yl)methylamino]methyl)piperidin-1-yl]methanone

| image = Befiradol.svg

| tradename =

| pregnancy_category =

| legal_status = Uncontrolled

| routes_of_administration =

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

| index_label =

| index2_label =

| IUPHAR_ligand = 3925

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 208110-64-9

| ATC_prefix = none

| ATC_suffix =

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 45305

| PubChem = 9865384

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = RAT9OHA1YH

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 8041076

| smiles = Cc1ccc(nc1)CNCC2(CCN(CC2)C(=O)c3ccc(c(c3)Cl)F)F

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = PKZXLMVXBZICTF-UHFFFAOYSA-N

| C=20 | H=22 | Cl=1 | F=2 | N=3 | O=1

}}

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-HT_1A receptor full agonist.

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.{{cite journal | vauthors = Newman-Tancredi A, Martel JC, Cosi C, Heusler P, Lestienne F, Varney MA, Cussac D | title = Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT_1A receptor agonist | journal = The Journal of Pharmacy and Pharmacology | volume = 69 | issue = 9 | pages = 1178–1190 | date = September 2017 | pmid = 28612503 | doi = 10.1111/jphp.12762 | s2cid = 13676820 }} In rat hippocampal membranes it preferentially activates GalphaO proteins. 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.{{cite journal | vauthors = Lladó-Pelfort L, Assié MB, Newman-Tancredi A, Artigas F, Celada P | title = In vivo electrophysiological and neurochemical effects of the selective 5-HT1A receptor agonist, F13640, at pre- and postsynaptic 5-HT1A receptors in the rat | journal = Psychopharmacology | volume = 221 | issue = 2 | pages = 261–272 | date = May 2012 | pmid = 22147258 | doi = 10.1007/s00213-011-2569-9 | s2cid = 18779324 }} In rat models, 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.{{cite journal | vauthors = Bardin L, Tarayre JP, Malfetes N, Koek W, Colpaert FC | title = Profound, non-opioid analgesia produced by the high-efficacy 5-HT(1A) agonist F 13640 in the formalin model of tonic nociceptive pain | journal = Pharmacology | volume = 67 | issue = 4 | pages = 182–194 | date = April 2003 | pmid = 12595749 | doi = 10.1159/000068404 | s2cid = 25882138 }}{{cite journal | vauthors = Bruins Slot LA, Koek W, Tarayre JP, Colpaert FC | title = Tolerance and inverse tolerance to the hyperalgesic and analgesic actions, respectively, of the novel analgesic, F 13640 | journal = European Journal of Pharmacology | volume = 466 | issue = 3 | pages = 271–279 | date = April 2003 | pmid = 12694810 | doi = 10.1016/S0014-2999(03)01566-8 }}{{cite journal | vauthors = Bardin L, Assié MB, Pélissou M, Royer-Urios I, Newman-Tancredi A, Ribet JP, Sautel F, Koek W, Colpaert FC | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 312 | issue = 3 | pages = 1034–1042 | date = March 2005 | pmid = 15528450 | doi = 10.1124/jpet.104.077669 | s2cid = 42446435 }}{{cite journal | vauthors = Colpaert FC, Deseure K, Stinus L, Adriaensen H | title = High-efficacy 5-hydroxytryptamine 1A receptor activation counteracts opioid hyperallodynia and affective conditioning | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 316 | issue = 2 | pages = 892–899 | date = February 2006 | pmid = 16254131 | doi = 10.1124/jpet.105.095109 | s2cid = 8820667 }}{{cite journal | vauthors = Deseure K, Bréand S, Colpaert FC | title = 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 | journal = European Journal of Pharmacology | volume = 568 | issue = 1–3 | pages = 134–141 | date = July 2007 | pmid = 17512927 | doi = 10.1016/j.ejphar.2007.04.022 }}

A structure–activity relationship (SAR) study revealed that replacement of the dihalophenyl moiety by 3-benzothienyl increases maximal efficacy from 84% to 124% (K_i=2.7 nM).{{cite journal | vauthors = Bollinger S, Hübner H, Heinemann FW, Meyer K, Gmeiner P | title = Novel pyridylmethylamines as highly selective 5-HT(1A) superagonists | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 19 | pages = 7167–7179 | date = October 2010 | pmid = 20860381 | doi = 10.1021/jm100835q }}{{cite journal | vauthors = Vacher B, Bonnaud B, Funes P, Jubault N, Koek W, Assié MB, Cosi C, Kleven M | title = Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors | journal = Journal of Medicinal Chemistry | volume = 42 | issue = 9 | pages = 1648–1660 | date = May 1999 | pmid = 10229633 | doi = 10.1021/jm9806906 | citeseerx = 10.1.1.325.8872 }}

History

Befiradol was discovered and developed by Pierre Fabre Médicament, a French pharmaceuticals company who initially developed it as a treatment for chronic pain. In September 2013, befiradol was out-licensed to Neurolixis, a US-based biotechnology company. Neurolixis announced that it intended to re-purpose befiradol for the treatment of levodopa-induced dyskinesia in Parkinson's disease.{{cite web | title = Neurolixis Announces In-Licensing of Two Clinical Compounds From Pierre Fabre Medicament

| date = 23 September 2013 | publisher = Neurolixis, Inc. | url = http://neurolixis.com/images/stories/nlx_pf_license_23sept13.pdf }} In support of this indication, Neurolixis received several research grants{{cite web|url=https://www.michaeljfox.org/foundation/funded-grants.php?srch=Neurolixis&x=0&y=0&from=2000&to=&country=&institution=&researcher=|title=Parkinson's Disease Grants funded by the Michael J. Fox Foundation {{!}} Parkinson's Disease|website=The Michael J. Fox Foundation for Parkinson's Research {{!}} Parkinson's Disease|access-date=2017-06-23}} from the Michael J. Fox Foundation and preclinical data was published describing the activity of befiradol in animal models of Parkinson's disease.{{cite journal | vauthors = Iderberg H, McCreary AC, Varney MA, Kleven MS, Koek W, Bardin L, Depoortère R, Cenci MA, Newman-Tancredi A | title = NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat | journal = Experimental Neurology | volume = 271 | pages = 335–350 | date = September 2015 | pmid = 26037043 | doi = 10.1016/j.expneurol.2015.05.021 | s2cid = 35525495 }}{{cite journal | vauthors = McCreary AC, Varney MA, Newman-Tancredi A | title = The novel 5-HT1A receptor agonist, NLX-112 reduces l-DOPA-induced abnormal involuntary movements in rat: A chronic administration study with microdialysis measurements | journal = Neuropharmacology | volume = 105 | pages = 651–660 | date = June 2016 | pmid = 26777281 | doi = 10.1016/j.neuropharm.2016.01.013 | s2cid = 1979117 }} 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.{{cite journal | vauthors = Depoortere R, Johnston TH, Fox SH, Brotchie JM, Newman-Tancredi A | title = The selective 5-HT_1A receptor agonist, NLX-112, exerts anti-dyskinetic effects in MPTP-treated macaques | journal = Parkinsonism & Related Disorders | volume = 78 | pages = 151–157 | date = September 2020 | pmid = 32846366 | doi = 10.1016/j.parkreldis.2020.08.009 | s2cid = 221343904 }}{{cite journal | vauthors = Fisher R, Hikima A, Morris R, Jackson MJ, Rose S, Varney MA, Depoortere R, Newman-Tancredi A | title = The selective 5-HT_1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets | journal = Neuropharmacology | volume = 167 | pages = 107997 | date = May 2020 | pmid = 32057799 | pmc = 7103782 | doi = 10.1016/j.neuropharm.2020.107997 }} 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.{{cite web|url=https://www.parkinsons.org.uk/news/investing-new-treatment-dyskinesia|title=Investing in a new treatment for dyskinesia | date = 24 January 2018 | publisher = Parkinson's UK }}

Clinical Ph2A Trial for dyskinesia in Parkinson's disease

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.{{cite web|url=https://www.prlog.org/12758787-fda-approves-neurolixis-ind-application-for-clinical-trial-with-nlx-112-in-parkinsons-disease.html|title=FDA Approves Neurolixis IND Application for a Clinical Trial with NLX-112 in Parkinson's Disease | date = 12 March 2019 | publisher = Neurolixis, Inc. | via = PRLog }}

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.{{cite news | vauthors = Gregory A | date = 22 November 2020 | work = The Times |url=https://www.thetimes.com/uk/science/article/life-changing-drug-to-calm-parkinsons-twitches-set-for-human-trials-pj6xqxfg7|title = 'Life-changing' drug to calm Parkinson's twitches set for human trials}} On 23 November 2020, Parkinson's UK and Michael J. Fox Foundation, confirmed their funding in an official announcement.{{cite press release|url=https://www.prnewswire.com/news-releases/global-charities-join-forces-to-drive-forward-new-drug-for-parkinsons-301178988.html|title = Global charities join forces to drive forward new drug for Parkinson's | work = The Michael J. Fox Foundation for Parkinson's Research | via = Cision US Inc }} Neurolixis announced on 30 November 2021 the start of patient recruitment in the clinical trial. The trial is listed on the U.S. National Library of Medicine clinical trials register.{{ClinicalTrialsGov|NCT05148884|Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in L-dopa-induced Dyskinesia}} On 20 March 2023, a joint press release from Neurolixis, Parkinson's UK and Michael J. Fox Foundation announced that the clinical trial had met its primary endpoint of safety and tolerability, and also the secondary endpoint of efficacy in reducing Levodopa-induced dyskinesia in the patients.{{cite web|url=https://www.einnews.com/pr_news/622375270/neurolixis-announces-positive-ph2a-proof-of-concept-on-nlx-112-in-levodopa-induced-dyskinesia-in-parkinson-s-disease|title = Neurolixis Announces Positive Ph2A Proof-of-Concept on NLX-112 in Levodopa-Induced Dyskinesia in Parkinson's Disease |date = 20 March 2023 | via = Newsmatics Inc }} Moreover, a later announcement (7 July 2023) disclosed that the clinical trial had also found that befiradol reduced parkinsonism symptoms (such as slowness of movement, tremor and rigidity), as well as Levodopa-induced dyskinesia, raising the prospect of developing a "dual-efficacy therapy" for Parkinson's disease.{{cite news |url= https://www.independent.co.uk/news/health/parkinsons-disease-drug-treatment-trial-b2370993.html |title= Researchers hopeful of treatment of Parkinson's by 2030 with 'dual efficacy' drug |last=Massey |first=Nina |date= 7 July 2023 |website= |work=The Independent |access-date=26 July 2023 }}

<sup>18</sup>F-Befiradol as an agonist PET radiotracer for brain imaging

As well as studies on befiradol for treatment of movement disorders, other researchers have investigated it as a novel radiotracer for brain imaging studies by positron emission tomography. Thus befiradol labeled with [18F] (also known as 18F-F13640) has been used to study the distribution of serotonin 5-HT1A receptors in rat, cat, macaque and human. Because befiradol is an agonist, it enables the detection of 5-HT1A receptors which are specifically in a functionally active state, whereas antagonist radiotracers label the total receptor population.{{cite journal | vauthors = Colom M, Vidal B, Fieux S, Redoute J, Costes N, Lavenne F, Mérida I, Irace Z, Iecker T, Bouillot C, Billard T, Newman-Tancredi A, Zimmer L | title = [¹⁸F]F13640, a 5-HT_1A Receptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations | journal = Frontiers in Neuroscience | volume = 15 | pages = 622423 | date = 2021 | pmid = 33762906 | pmc = 7982540 | doi = 10.3389/fnins.2021.622423 | doi-access = free }}{{cite journal | vauthors = Courault P, Lancelot S, Costes N, Colom M, Le Bars D, Redoute J, Gobert F, Dailler F, Isal S, Iecker T, Newman-Tancredi A, Merida I, Zimmer L | title = [¹⁸F]F13640: a selective agonist PET radiopharmaceutical for imaging functional 5-HT_1A receptors in humans | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 50 | issue = 6 | pages = 1651–1664 | date = May 2023 | pmid = 36656363 | pmc = 10119077 | doi = 10.1007/s00259-022-06103-1 }}