Flesinoxan

Flesinoxan (DU-29,373) is a potent and selective 5-HT1A receptor partial/near-full agonist of the phenylpiperazine class.[1][2][3] Originally developed as a potential antihypertensive drug,[1][2][4] flesinoxan was later found to possess antidepressant and anxiolytic effects in animal tests.[5][6] As a result, it was investigated in several small human pilot studies for the treatment of major depressive disorder, and was found to have robust effectiveness and very good tolerability.[7][8] However, due to "management decisions", the development of flesinoxan was stopped and it was not pursued any further.[9]

Flesinoxan
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Identifiers
IUPAC name
  • 4-fluoro-N-(2-{4-[(2S)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperazin-1-yl}ethyl)benzamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC22H26FN3O4
Molar mass415.465 g·mol−1
3D model (JSmol)
SMILES
  • C1CN(CCN1CCNC(=O)C2=CC=C(C=C2)F)C3=C4C(=CC=C3)O[C@H](CO4)CO
InChI
  • InChI=1S/C22H26FN3O4/c23-17-6-4-16(5-7-17)22(28)24-8-9-25-10-12-26(13-11-25)19-2-1-3-20-21(19)29-15-18(14-27)30-20/h1-7,18,27H,8-15H2,(H,24,28)/t18-/m0/s1
  • Key:NYSDRDDQELAVKP-SFHVURJKSA-N

In patients, flesinoxan enhances REM sleep latency, decreases body temperature, and increases ACTH, cortisol, prolactin, and growth hormone secretion.[2][8]

Synthesis
  • See also for Halopemide (same sidechain).
Synthesis:[10] Patent:[11]

The nitration of Catechol (1) with nitric acid gave 2-Nitrocatechol [3316-09-4] (2). The treatment with epichlorohydrin/NaOH (not glycerol) gave #. Acetylation with acetyl chloride gave (5-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl acetate [145124-52-3] (3). The reduction of the nitro group by catalytic hydrogenation led to (5-amino-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl acetate [145124-55-6] (4). Piperazine formation with Bis(2-chloroethyl)amine hydrochloride [821-48-7] (5) gave [145124-53-4] (6). Amide formation with 1-(4-fluorobenzoyl)aziridine [15257-81-5] (7) completed the synthesis of Flesinoxan (8).

See also

References
  1. Schoeffter P, Hoyer D (November 1988). "Centrally acting hypotensive agents with affinity for 5-HT1A binding sites inhibit forskolin-stimulated adenylate cyclase activity in calf hippocampus". British Journal of Pharmacology. 95 (3): 975–85. doi:10.1111/j.1476-5381.1988.tb11728.x. PMC 1854240. PMID 3207999.
  2. Pitchot W, Wauthy J, Legros JJ, Ansseau M (March 2004). "Hormonal and temperature responses to flesinoxan in normal volunteers: an antagonist study". European Neuropsychopharmacology. 14 (2): 151–5. doi:10.1016/S0924-977X(03)00108-1. PMID 15013031. S2CID 19082134.
  3. Hadrava V, Blier P, Dennis T, Ortemann C, de Montigny C (October 1995). "Characterization of 5-hydroxytryptamine1A properties of flesinoxan: in vivo electrophysiology and hypothermia study". Neuropharmacology. 34 (10): 1311–26. doi:10.1016/0028-3908(95)00098-Q. PMID 8570029. S2CID 27967032.
  4. Wouters W, Tulp MT, Bevan P (May 1988). "Flesinoxan lowers blood pressure and heart rate in cats via 5-HT1A receptors". European Journal of Pharmacology. 149 (3): 213–23. doi:10.1016/0014-2999(88)90651-6. PMID 2842163.
  5. van Hest A, van Drimmelen M, Olivier B (1992). "Flesinoxan shows antidepressant activity in a DRL 72-s screen". Psychopharmacology. 107 (4): 474–9. doi:10.1007/BF02245258. PMID 1351303. S2CID 6258207.
  6. Rodgers RJ, Cole JC, Davies A (August 1994). "Antianxiety and behavioral suppressant actions of the novel 5-HT1A receptor agonist, flesinoxan". Pharmacology, Biochemistry, and Behavior. 48 (4): 959–63. doi:10.1016/0091-3057(94)90205-4. PMID 7972301. S2CID 39446719.
  7. Grof P, Joffe R, Kennedy S, Persad E, Syrotiuk J, Bradford D (1993). "An open study of oral flesinoxan, a 5-HT1A receptor agonist, in treatment-resistant depression". International Clinical Psychopharmacology. 8 (3): 167–72. doi:10.1097/00004850-199300830-00005. PMID 8263314. S2CID 33325915.
  8. Ansseau M, Pitchot W, Moreno AG, Wauthy J, Papart P (2004). "Pilot study of flesinoxan, a 5-HT1A agonist, in major depression: Effects on sleep REM latency and body temperature". Human Psychopharmacology: Clinical and Experimental. 8 (4): 279–283. doi:10.1002/hup.470080407. S2CID 145758823.
  9. Celada P, Bortolozzi A, Artigas F (September 2013). "Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research". CNS Drugs. 27 (9): 703–16. doi:10.1007/s40263-013-0071-0. PMID 23757185. S2CID 31931009.
  10. Ennis, Michael D.; Ghazal, Nabil B. (1992). "The synthesis of (+)-and (−)-flesinoxan: Application of enzymatic resolution methodology". Tetrahedron Letters 33 (42): 6287–6290. doi:10.1016/S0040-4039(00)60954-1.
  11. EP0138280 idem Jan Hartog, Wouter Wouters, Lneke van Wijngaarden, U.S. Patent 4,833,142 (1989 to Duphar International Research B.V.).
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