Phenserine

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Phenserine
Clinical data
Other names(-)-Phenserine, (-)-Eseroline phenylcarbamate, N-phenylcarbamoyleseroline, N-phenylcarbamoyl eseroline
Routes of
administration		By mouth
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Bioavailability~100% [1]
Metabolismliver
Metabolites(−)-N1-norphenserine, (−)-N8-norphenserine, (−)-N1,N8-bisnorphenserine
Elimination half-life12.6 minutes
Duration of action8.25 hours [2]
Excretionrenal or hepatic clearance [2]
Identifiers
  • (3a'S,8aR)-1,3a,8-Trimethyl-1H,2H,3H,3aH,8H,8aH-pyrrolo[2,3-b]indol-5-yl N-phenylcarbamate
JSmol)
Melting point150 °C (302 °F)
  • [H][C@]12N(C)CC[C@@]1(C)C1=C(C=CC(OC(=O)NC3=CC=CC=C3)=C1)N2C
  • InChI=InChI=1S/C20H23N3O2/c1-20-11-12-22(2)18(20)23(3)17-10-9-15(13-16(17)20)25-19(24)21-14-7-5-4-6-8-14/h4-10,13,18H,11-12H2,1-3H3,(H,21,24)/t18-,20+/m1/s1
  • Key:PBHFNBQPZCRWQP-QUCCMNQESA-N

Phenserine (also known as (-)-phenserine or (-)-eseroline phenylcarbamate) is a synthetic drug which has been investigated as a medication to treat Alzheimer's disease (AD), as the drug exhibits neuroprotective and neurotrophic effects.

The research of phenserine, initially patented by the

methodological issues that were not impeccably settled before proceeding to the subsequent clinical phases.[5][6]

Phenserine was introduced as an

cognitive functions of the brain.[7] The ameliorative mechanism involves both cholinergic and non-cholinergic pathways.[8][9]

The clinical translatable doses of phenserine show relatively high tolerability and rarely manifest severe adverse effects.[10] With respect to overdosing of the drug (20 mg/kg), a few cholinergic adverse effects were reported, including nausea and tremor which are not life-threatening.[11]

An administration form of phenserine, (-)-phenserine tartrate, which exhibits high bioavailability and solubility, is taken by mouth. Phenserine and its metabolites can readily access the brain with high permeability across the blood-brain barrier and sustain to act for a long duration with the relatively short half-life. Posiphen ((+)-phenserine), the enantiomer of (-)-phenserine, is also a potential drug by itself or synergically with (-)-phenserine, to mitigate the progression of neurological diseases, mainly Alzheimer's disease.[3]

History

Phenserine was first investigated as a substitute for

double-blinded, placebo-controlled and 7-month phase III trial which had been conducted on 377 mild to moderate Alzheimer's disease patients across Austria, Croatia, Spain, and UK[5] ̶ were discovered and no significance was exhibited for the drug efficacy. This led to the relinquishment of phenserine development,[5]
merely displaying its marketable potential.

Approval status

Phenserine failed in phase III of Alzheimer's disease-aimed clinical trials and there has yet been no promise of the trial resumption since 2006.[5] The methodological problems of trials are frequently speculated as the principal reason for the failure of FDA approval as well as the scarcity of Alzheimer's disease drugs.[6] The underlying complications are generated by an inordinate variance in clinical outcomes and poor determination in optimal dosing.[5][6]

Intra and inter-site variations were incurred by a lack of baseline evaluation and longitudinal assessment on placebo groups.[6] This produced an inadequate power and, thus, appeared to have insufficient statistical significance. In light of the dose determination, the criteria for human subject engagement was not meticulously established before dosing and the effective dose range was not completely established in phase I and II, yet still persisting to phase III.[5] Compared to other Alzheimer's disease drugs, such as donepenzil, tacrine and metrifonate, the clinical advancement of phenserine involves comparably high compliance in outcome measures and protocol regimentation on methods and the clinical phase transition.[5]

Pharmacological benefits

Phenserine was invented as the Alzheimer's disease-oriented treatment in particular, and also proven to have alleviative effects upon other neurological disorders,

hypoxic brain injuries[8][9][10] The traumatic brain injuries have been substantially examined and induced to form test groups in phenserine research.[10][17]
They are highly correlated with the onset of neurodegenerative disorders, precipitating cognitive, and behavioral impairments.

Phenserine was proven to mitigate the multiple cascades of neuropathology, triggered by traumatic brain injuries, via both cholinergic and non-cholinergic mechanisms.[8][9]

Pharmacodynamics (mechanism of action)

Cholinergic mechanism

AChE mechanism of action in the synaptic cleft and how phenserine inhibits the AChE

Phenserine serves as an

hydrolyzed by the enzyme and enables the neurotransmitter to be further retained at the synaptic clefts.[18] Such mechanism promotes the cholinergic neuronal circuits to be activated and thereby enhances memory and cognition in Alzheimer's subjects.[17]

Non-cholinergic mechanism

β-Amyloid (Aβ) plaque formation from β-amyloid precursor protein (APP)

In clinical trials, phenserine was demonstrated to alleviate

neurodegeneration, repressing the programmed neuronal cell death and enhancing the stem cell survival and differentiation. The alleviation can be achieved by increase in levels of neurotrophic BDNF and anti-apoptotic protein, Bcl-2, which subsequently reduces expressions of pro-apoptotic factors, GFAP and activates caspase 3.[4][8] The treatment also suppresses the levels of Alzheimer's disease-inducing proteins which are β-amyloid precursor protein (APP)[19] and Aβ peptide.[8][20] The drug interaction with the APP gene mediates the expression of both APP and its following product, Aβ protein. This regulating action reverses the glial cell-favored differentiation and increases the neuronal cell output.[17]

Phenserine also attenuates the

TNF-α.[10] The disrupted integrity of the blood brain barrier by a degrading chemical, MMP-9, leading to neuroinflammation, is restored by phenserine as well.[8]

The

protein misfolding, are highly observed in Parkinson's disease. The drug therapy was proven to neutralize the toxicity of alpha-synucleins via protein translation, alleviating the symptoms of the disease.[9]

Dosage

Clinically, the translatable dose of phenserine was primarily employed within a range of 1 to 5 mg/kg where the unit calibration took account of the body surface area.[4][8] This standard dose range was generally well tolerated in long term trials[10] by neuronal cell cultures, animal models and humans. Increment in dosing by 10 mg/kg is still tolerated without instigating any physiological implication.[2] The maximal administration of phenserine up to 15 mg/kg was reported in rats.[2]

Overdose

The dose of 20 mg/kg and above are appraised as overdosing in which cholinergic adverse effects ensue.

The symptoms of overdosing includes:[11]

Mild symptoms were notified in clinical trials but no other seriously considerable adverse effects were expressed.[5] Tremor was also noted as one of the dose-limiting actions.[2]

Chemistry

Pharmacokinetics

Oral bioavailability of phenserine was shown to be very high, up to 100%. Its bioavailability was tested by computing the drug's delivery rate across the rat's blood brain barrier.[22] The drug concentration, reached in the brain, is 10-fold higher than plasma levels,[23] verifying phenserine as a brain-permeable AChE inhibitor.[24]

Relative to its short plasma half life of 8 to 12 minutes, phenserine exhibits a long duration of action with the half-life of 8.25 hours in which the hindering effect on AChE is time-dependently faded. With the administration of phenserine, 70% or higher AChE inhibitory action in the blood was observed in preclinical studies and with systemic phenserine administration, the extracellular ACh level in the striatum increased up to three times.[24] Through PET studies and microdialysis, the compound's brain permeability was able to be further elucidated.[25]

Enantiomer (posiphen)

Further information: Buntanetap
Comparison of the chemical structures of phenserine (left) and posiphen (right)

(-)-Phenserine, generally referred to phenserine, acts as an active enantiomer for the inhibition of acetylcholinesterase (AChE) while posiphen, its alternative enantiomer, was comparably demonstrated as a poor AChE inhibitor.[26]

In the history of posiphen research, several companies were interactively involved. In 2005, an Investigational New Drug (IND) application of posiphen was filed with FDA by TorreyPines Therapeutics while its phase I trial on animal models had been implemented by Axonyx.[27] Axonyx and TorreyPines Therapeutics officially signed for their merger agreement[27] in 2006 and licensed the drug to QR Pharma in 2008.[28] The clinical trials of posiphen against Alzheimer's disease are still underway.

Interactions

Currently, 282 drugs have been reported to make interactions with phenserine.[29][30]

Current research

A 5-year double blinded, donepezil-controlled clinical study for validation of Alzheimer's disease course modification using phenserine has been undertaken as from 2018, involving 200 patients in the UK and US. The study aims to reduce variation in AD therapeutic response between patients via optimal dose formulation.[4]

References

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  11. ^ a b Sugaya K (2015-04-08). "A method of biasing implanted human neural stem cells away from differentiation into glial cells by (+) phenserine to modulate the concentration of soluble ßapp in tissue or csf". Ucf Patents.
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  13. ^ "Axonyx Announces License of Phenserine to Daewoong Pharmaceutical Company for South Korea". www.businesswire.com. 2006-01-04. Retrieved 2020-04-06.
  14. ^ "Phenserine - Next Generation AChE Inhibitor". Clinical Trials Arena. Retrieved 2020-04-06.
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  23. OCLC 1058877507. {{cite book}}: |last= has generic name (help)CS1 maint: multiple names: authors list (link
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  27. ^ a b "Axonyx and TorreyPines Therapeutics Announce Merger Agreement; Transaction Creates Robust Portfolio in the CNS Disease Area". www.businesswire.com. 2006-06-08. Retrieved 2020-04-08.
  28. ^ "TorreyPines Therapeutics licenses Posiphen, bisnorcymcerine, phenserine to QR Pharma - Quick Facts". RTTNews. Retrieved 2020-04-08.
  29. ^ "Phenserine". www.drugbank.ca. Retrieved 2020-04-27.
  30. PMID 29126136
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