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| Clinical data | |
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| Other names | (+/-)-(trans)-5-fluoro-2,3,3a,9a-tetrahydro-1H-[1,4]benzodioxino[2,3-c]pyrrole hydrochloride hemihydrate |
| Routes of administration | Oral |
| Pharmacokinetic data | |
| Bioavailability | 85% oral from tablet formulation |
| Metabolism | Greater than 90% excreted as (sulphamic acid and carbamoyI glucuronide conjugates) |
| Eliminationhalf-life | 6 hours |
| Excretion | Renal |
| Identifiers | |
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| CompTox Dashboard(EPA) |
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| Chemical and physical data | |
| Formula | C10H12ClFNO2.5 |
| Molar mass | 240.66 g·mol−1 |
| 3D model (JSmol) |
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Fluparoxan (developmental code nameGR50360A) is a potentα2-adrenergic receptorantagonist (pKB = 7.9) with excellentselectivity for this receptor over theα1-adrenergic receptor (2,630-fold), and is the only well-studied α2-adrenergic receptor antagonist in its structural family which does not antagonize any variant of theimidazoline receptor.[1][2] It was shown to possess central α2-adrenoceptor antagonist activity after oral doses in man and was patented as anantidepressant byGlaxo in the early 1980s, but its development was discontinued when the compound failed to show a clear clinical advantage over existing therapies.[1]
Fluparoxan is a very selective α2-adrenergic blocker,[3] that readily crosses the blood–brain barrier. Blockade of α2-adrenoreceptors, particularlypresynapticautoreceptors innoradrenergicneurons by fluparoxan, produces an increase in the synaptic concentrations of noradrenaline,[4] by blocking the autoinhibitory feedback mechanism. This release of noradrenaline has a potential value in the treatment of disorders which are associated with a deficiency ofnoradrenaline atpostsynapticadrenoreceptors, such as depression,[5] the early features ofAlzheimer's disease and schizophrenia and other neurodevelopmental disorders associated with cognitive impairment.[6][7] Fluparoxan also exhibits noanticholinergic,antidopaminergic, α1-adrenergic,β-adrenergic,muscarinic, or5-HT1 receptor-blocking effects.[3]
Fluparoxan showed α2-adrenoceptors antagonist activity in vivo in several animal species.[3] In the conscious mouse, fluparoxan was effective by the oral route in preventingclonidine-inducedhypothermia andantinociception. While in the rat the marked impairment of rotarod performance were prevented dose-dependently by fluparoxan. Fluparoxan, orally prevented agonist UK-14304 induced sedation andbradycardia in a dose-related fashion in the dog. Fluparoxan has been shown to possess central α2-adrenoceptor antagonist activity after both single and repeated oral doses in man, significantly attenuating all responses to the agonist clonidine (growth hormone secretion, bradycardia,hypotension,xerostomia) apart from the measures of sedation.[8]
Fluparoxan has shown positive effects in the treatment of cognitive dysfunction in schizophrenia patients when orally dosed with fluparoxan,[1] and in the treatment of central neurodegenerative disorders in models of Alzheimer's disease where it prevented age-related decline in spatial working memory intransgenic mice, although it had no effect in other memory tasks such as object recognition or theMorris water maze and occurred in the absence of obvious concomitant change in pathology such asβ-amyloid plaque load andastrocytosis.[9]
The individualchiral isomers7 (+) 3aR,9aR and8 (-) 3aS,9aS of fluparoxan both had comparable levels of α2-adrenoceptors antagonist potency and α2/α1 selectivity toracemic fluparoxan6 (±)rel 3aR,9aR in vitro and a similar potency in vivo in reversing the hypothermia induced in mice by clonidine.[3]
Enantiomer_and_(-)Enantiomer.svg)
| Compound as HCl | α2-Adrenoceptors Vas deferens UK14304 | α1-Adrenoceptors Anococcygeus muscle Phenylephrine | Hypothermia Clonidine Mice po | Optical Rotation | Melting Point |
|---|---|---|---|---|---|
| Measurement | pKB | pKB | ED50mg/kg | [α]20-23D° | mp°C |
| 6 (+/-)rel 3aR,9aR | 7.86 | 5.00 | 0.66 | 0 | 245 |
| 7 (+) 3aR,9aR | 7.88 | 4.47 | 0.73 | +159.6 | 235-236 |
| 8 (-) 3aS,9aS | 7.68 | 4.95 | 0.46 | -159.4 | 238-240 |
Fluparoxan has rat and human protein binding of 81-92% and 95% respectively. Fluparoxan shows high in vitro permeability in MCDK (Papp nm/s =2500) andCaco-2 (Papp nm/s =2000) cells which correlates well with the known high oral intestinal absorption (100%) in humans.[10]Fluparoxan is well absorbed following oral dosing in all animals. Clearance was largely metabolic, with both oral and intravenous doses being excreted mainly via the urine (> 90%, of administered dose), chiefly as phase II metabolites (sulphamic acid and carbamoyIglucuronide conjugates).[11] Fluparoxan has high oralbioavailability (100%) and a long duration of action (2hr) in the rat,[1] which accounts for its similar potency seen by both the oral and intravenous routes of administration in this species.[3] The excellent pharmacokinetics exhibited by fluparoxan in animals also translated into man[1] where it has a superior bioavailability (97%) and longer duration of action (6-7hrs).
Fluparoxan was not metabolized by humancytochrome P450 enzymes CYP1A and CYP2A, and was found not to be a mutagen in cultured human peripherallymphocytes and did not cause gene mutation when administered to Chinese hamsterfibroblasts in culture.[11] No mutagenic potential was identified in microbiological mutagenicity tests including a fluctuation test with S9 activation. No hydroxylated metabolites were identified after incubation with rat livermicrosomes (S9) or in rat urine following oral dosing.[1] The compound was well tolerated on repeat oral administration to rat (≤ 200 mg /kg/day) and dog (≤ 80 mg/kg/day) for 12 months.
Racemic (±) fluparoxan6 is a white crystalline powder as the hydrochloride hemihydrate m.p. 245 °C.[1] It is a mixture of twoenantiomers and is moderately lipophilic (log P = 1.2) with good solubility 80 mg/mL in water at 25 °C. The compound is very stable in the solid state and its bioavailability from tablet formulation is 85% and absorption is rapid.[1]
Racemic (±) fluparoxan6 was first synthesised by a convergent route,[1][2] which involved converting the bis-benzyl ether of cis-butene-l,4-diol1 into its epoxide2 followed by acid catalyzed ring opening to a racemic-diol which was then converted into the racemic trans bis-tosylate3. Coupling 3-fluorocatechol4 with the racemic trans bis-tosylate3 in the presence base gave on deprotection the benzodioxan diol5 which was converted to racemic6 via coupling its bis-mesylate to benzylamine followed by deprotection.[1][2]
The individual chiral isomers (+)7 and (-)8 of fluparoxan were originally prepared from the (+) and (-) isomers ofdiethyl tartrate via the corresponding chiral trans bis-tosylates in a convergent route similar to that shown in the synthesis of racemic fluparoxan.[1]
Although fluparoxan has been shown to possess central α2-adrenoceptor antagonist activity after both single and repeated oral doses in man, clinical evaluation in depression and its development for the treatment of male sexual dysfunction was discontinued in the early 1990s when the compound failed to show a clear clinical advantage over existing therapies. The same is true for other α2-adrenoceptor antagonists in depression and it is now generally agreed that the original hypothesis that blocking α2-presynaptic adrenoceptors to increase brain levels of noradrenalin is insufficient as a neurobiological basis for depressive disorders, with the true picture likely to be much more complex and heterogeneous, involving bothmonoaminergic and nonmonoaminergic players.[12] In contrast however, recent interest in fluparoxan has increased with its positive effects in treating cognitive dysfunction in centralneurodegenerative diseases.[1]
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