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F-15599

From Wikipedia, the free encyclopedia
Chemical compound
Pharmaceutical compound
F-15599
Clinical data
Other namesF-15599; F15599; NLX-101; NLX101
Routes of
administration		Oral
Drug classSerotonin5-HT1A receptoragonist
Legal status
Legal status
  • Investigational
Pharmacokinetic data
MetabolismDB16936DB16936
Identifiers
  • 3-Chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin-1-yl]methanone
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard(EPA)
Chemical and physical data
FormulaC19H22ClF2N4O
Molar mass395.86 g·mol−1
3D model (JSmol)
  • Cc3cnc(nc3)CNCC(F)(CC2)CCN2C(=O)c(cc1Cl)ccc1F
  • InChI=1S/C19H21ClF2N4O/c1-13-9-24-17(25-10-13)11-23-12-19(22)4-6-26(7-5-19)18(27)14-2-3-16(21)15(20)8-14/h2-3,8-10,23H,4-7,11-12H2,1H3 ☒N
  • Key:WAAXKNFGOFTGLP-UHFFFAOYSA-N ☒N
  (verify)

F-15,599, also known asNLX-101, is apotent andselective5-HT1A receptorfull agonist.[1][2] In addition, it displaysfunctional selectivity, orbiased agonism, by preferentially activatingpostsynaptic serotonin 5-HT1A receptors oversomatodendritic serotonin 5-HT1Aautoreceptors.[3][1][2] The drug has been investigated for potential use as apharmaceutical drug in the treatment of conditions includingdepression,schizophrenia,cognitive disorders,Rett syndrome, andfragile X syndrome.[4]

Pharmacology

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Pharmacodynamics

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In terms of itsfunctional selectivity, the drug preferentially activates andphosphorylatesERK1/2 overreceptorinternalization or inhibition ofadenylyl cyclase.[3] In addition, it preferentially activates theGαiG protein subtype over the Gαo subtype.[3] As a result of itsbiased agonism forpostsynaptic 5-HT1A receptors, F-15,599 showsregional selectivity in itscentral effects.[3] It mainly activates theprefrontal cortex,cingulate cortex,retrosplenial cortex,septum, andcolliculi.[3] Conversely, the drug does not significantly altercerebral blood flow in areas characterized by abundance ofpresynaptic serotonin 5-HT1A receptors, such as theraphe nucleus.[3][1][2]

F-15,599 has shownantidepressant-like,anxiolytic-like,antidyskinetic,procognitive, andantiaggressive effects in animals.[3][1][2][5] Incognitive tests in rodents, F-15,599 attenuatesmemory deficits elicited by theNMDA receptor antagonistphencyclidine (PCP), suggesting that it may improvecognitive function in disorders such asschizophrenia.[6] Another study found that F-15,599 reducesbreathing irregularity andapneas observed in mice withmutations of theMeCP2gene, amouse model ofRett syndrome.[3][7]

History

[edit]

F-15,599 was first described in thescientific literature by 2006.[8]

Clinical trials

[edit]

F-15,599 was discovered and initially developed byPierre Fabre Médicament, a French pharmaceuticals company. In September 2013, F-15,599 was out-licensed toNeurolixis, a California-based biotechnology company. Neurolixis announced that it intends to re-purpose F-15,599 for the treatment ofRett syndrome.[9] and obtainedorphan drug designation from the United StatesFood and Drug Administration (FDA)[10] and from the European Commission for this indication.[11]

Researchers at theUniversity of Bristol are investigating the activity of F-15599 in animal models of Rett Syndrome, with support from the International Rett Syndrome Foundation.[12] In June 2015, the Rett Syndrome Research Trust awarded a grant to Neurolixis to advance F-15599 to clinical development.[13]

As of September 2024, F-15,599 is inphase 1clinical trials forfragile X syndrome.[4] Conversely, no recent development has been reported fordepressive disorders orRett syndrome and development has been discontinued forcognition disorders,mood disorders, andschizophrenia.[4]

See also

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References

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  1. ^abcdMaurel JL, Autin JM, Funes P, Newman-Tancredi A, Colpaert F, Vacher B (October 2007). "High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity".Journal of Medicinal Chemistry.50 (20):5024–33.doi:10.1021/jm070714l.PMID 17803293.
  2. ^abcdNewman-Tancredi A, Martel JC, Assié MB, et al. (January 2009)."Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist".British Journal of Pharmacology.156 (2):338–53.doi:10.1111/j.1476-5381.2008.00001.x.PMC 2697830.PMID 19154445.
  3. ^abcdefghSałaciak K, Pytka K (November 2021)."Biased agonism in drug discovery: Is there a future for biased 5-HT1A receptor agonists in the treatment of neuropsychiatric diseases?".Pharmacol Ther.227 107872.doi:10.1016/j.pharmthera.2021.107872.PMID 33905796.
  4. ^abc"NLX 101".AdisInsight. 28 September 2024. Retrieved26 October 2024.
  5. ^Assié MB, Bardin L, Auclair AL, et al. (November 2010)."F15599, a highly selective post-synaptic 5-HT(1A) receptor agonist: in-vivo profile in behavioural models of antidepressant and serotonergic activity".The International Journal of Neuropsychopharmacology.13 (10):1285–1298.doi:10.1017/S1461145709991222.PMID 20059805.
  6. ^Depoortère R, Auclair AL, Bardin L, Colpaert FC, Vacher B, Newman-Tancredi A (September 2010). "F15599, a preferential post-synaptic 5-HT1A receptor agonist: activity in models of cognition in comparison with reference 5-HT1A receptor agonists".European Neuropsychopharmacology.20 (9):641–654.doi:10.1016/j.euroneuro.2010.04.005.PMID 20488670.S2CID 22222213.
  7. ^Levitt ES, Hunnicutt BJ, Knopp SJ, Williams JT, Bissonnette JM (December 2013)."A selective 5-HT1a receptor agonist improves respiration in a mouse model of Rett syndrome".Journal of Applied Physiology.115 (11):1626–33.doi:10.1152/japplphysiol.00889.2013.PMC 3882741.PMID 24092697.
  8. ^Assié, M. B., Cosi, C., Slot, L. B., Cussac, D., Martel, J. C., Depoortere, R., ... & Newman-Tancredi, A. (2006, October). Pharmacological profile of F15599, a highly selective serotonin 5-HT1A receptor agonist. In Society for Neuroscience 36th Annual Meeting, Atlanta, Georgia, USA (pp. 14–18).https://scholar.google.com/scholar?cluster=13780243967428028494
  9. ^http://neurolixis.com/images/stories/nlx_pf_license_23sept13.pdf[full citation needed]
  10. ^"Enforcement Reports". Archived fromthe original on 2015-02-24. Retrieved2014-03-03.
  11. ^"Public Health - European Commission".
  12. ^"April: Rett syndrome research | News and features | University of Bristol".
  13. ^"RSRT Awards $530,000 to Neurolixis for Clinical Development of NLX-101". 24 June 2015.


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5-HT3–7
5-HT3
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