Buntanetap

Last updated
Buntanetap
Posiphen.svg
Clinical data
Trade names Posiphen, ANVS-401
Routes of
administration 		By mouth
Legal status
Legal status
  • Investigational
Identifiers
  • [(3aS,8bR)-3,4,8b-trimethyl-2,3a-dihydro-1H-pyrrolo[2,3-b]indol-7-yl] N-phenylcarbamate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H23N3O2
Molar mass 337.423 g·mol−1
3D model (JSmol)
  • C[C@]12CCN([C@H]1N(C3=C2C=C(C=C3)OC(=O)NC4=CC=CC=C4)C)C
  • 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+/m0/s1
  • Key:PBHFNBQPZCRWQP-AZUAARDMSA-N

Buntanetap (formerly known as posiphen) is an orally-administered small molecule translational inhibitor of aggregating neurotoxic proteins that is under investigation for the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. [1] [2] It is the (+) enantiomer of phenserine, which, unlike the (-) enantiomer, lacks the unwanted anticholinergic activity. [3] It is currently in Phase 3 clinical trial for early Alzheimer's disease and in the Open-Label Extension (OLE) study for Parkinson's disease. [4] [5]

Contents

Development

Different from monoclonal antibody therapies, buntanetap is an orally available small molecule with a unique mechanism of action: it inhibits the translation of multiple neurotoxic proteins at once, including amyloid precursor proteins (APP) and amyloid beta, tau, alpha-synuclein (αSYN), huntingtin, and TDP-43 [6] [7] [8] [9] . Buntanetap performs in a noncholinergic manner and works specifically in the conditions of high iron influx, often seen in damaged nerve cells, which trigger the overproduction of neurotoxic proteins. Specifically, high iron concentration leads to the release of mRNAs coding for neurotoxic proteins from Iron Regulatory Protein 1 (IRP1), allowing the free mRNA to be translated by the ribosomes [10] . High levels of neurotoxic proteins create a toxic cascade which results in faulty nerve cell functioning, impaired axonal transport and synaptic activity, and inflammation, eventually leading to nerve cell death. Buntanetap strengthens the binding of the mRNAs to IRP1, preventing them from being released and translated by the ribosome, thereby stopping translation and impeding the toxic cascade [11] [12] [13] .

Buntanetap is safe and well-tolerated at doses even 8 times higher than the efficacious dose. In vivo, the levels of APP protein in the cortex were reduced by buntanetap with an ED50 of 20mg/kg (median Effective Dose). [14] [15] The β-secretase activity in the mouse brain also could be reduced with elevated doses of 35 and 50 mg/kg. Overall, the dose range from 10 mg to 160 mg of buntanetap is well tolerated and generally adopted in clinical uses. With higher doses, supralinear increase of plasma levels was shown, indicating the saturable metabolism, which is a factor related to toxicity. Studies have shown that plasma levels of buntanetap reducing brain Aβ levels are equal or greater in humans than mice. [16] Once buntanetap is dosed over 160 mg, gastro-intestinal related symptoms including nausea and vomiting, were manifested. [16] The drug additionally presents the rapid absorption rate, occurred within an hour or two. Pharmacokinetics of buntanetap was overall kept linear.

See also

References

  1. ↑ Gubar M (11 January 2022). "Buntanetap: Breakthrough in Treatment of Alzheimer's and Parkinson's • BioPharma News". BioPharma News. Retrieved 13 January 2023.
  2. ↑ "As Buntanetap tartrate moves closer to clinical approval, what is the likelihood that the drug will be approved?". Pharmaceutical Technology. 30 December 2022. Retrieved 13 January 2023.
  3. ↑ Lahiri DK, Utsuki T, Shaw KT, Ge YW, Sambamurti K, Eder PS, et al. (2002). "Phenserine Regulates Translation of ß—Amyloid Precursor Protein Message". Mapping the Progress of Alzheimer's and Parkinson's Disease. Advances in Behavioral Biology. Vol. 51. pp. 211–215. doi:10.1007/978-0-306-47593-1_35. ISBN   978-1-4757-0973-5.
  4. ↑ "A Study of Buntanetap in Participants With PD". clinicaltrials.gov. 16 December 2025. Retrieved 5 January 2026.
  5. ↑ "A Double-blind Dual Study Assessing Safety and Efficacy of Buntanetap in Participants With Early AD". clinicaltrials.gov. 29 November 2024. Retrieved 5 January 2026.
  6. ↑ Teich, Andrew (18 January 2018). "Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse". Alzheimer's & Dementia: Translational Research & Clinical Interventions. 4: 37–45 – via PubMed Central.
  7. ↑ Kuo, Yien-Ming (15 February 2019). "Translational inhibition of α-synuclein by Posiphen normalizes distal colon motility in transgenic Parkinson mice". American Journal of Neurodegenerative Disease. 8 (1): 1–15 – via PubMed Central.
  8. ↑ Maccecchini, Maria (11 July 2012). "Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans". Journal of Neurology, Neurosurgery, and Psychiatry. 83 (9): 894–902 – via PubMed.
  9. ↑ Chen, Xu-Qiao (7 December 2021). "Posiphen Reduces the Levels of Huntingtin Protein through Translation Suppression". Pharmaceutics. 13 (12): 2109 – via PubMed Central.
  10. ↑ Cho, Hyun-Hee (8 October 2010). "Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1". The Journal of Biological Chemistry. 285 (41): 31217–32 – via PubMed.
  11. ↑ Bandyopadhyay, Sanghamitra (31 July 2013). "Novel 5' Untranslated Region Directed Blockers of Iron Regulatory Protein-1 Dependent Amyloid Precursor Protein Translation: Implications for Down Syndrome and Alzheimer's Disease". PLoS One. 8 (7) – via PubMed.
  12. ↑ Mikkilineni, Sohan (29 May 2012). "The anticholinesterase phenserine and its enantiomer posiphen as 5'untranslated-region-directed translation blockers of the Parkinson's alpha synuclein expression". Parkinson's Disease– via PubMed.
  13. ↑ Rogers, Jack (8 January 2011). "The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen". Journal of Neural Transmission. 118 (3): 493–507 – via PubMed.
  14. ↑ Klein J (July 2007). "Phenserine". Expert Opinion on Investigational Drugs. 16 (7): 1087–1097. doi:10.1517/13543784.16.7.1087. PMID   17594192. S2CID   219292296.
  15. ↑ Chen J, Pan H, Chen C, Wu W, Iskandar K, He J, et al. (2014-06-23). "(-)-Phenserine attenuates soman-induced neuropathology". PLOS ONE. 9 (6) e99818. Bibcode:2014PLoSO...999818C. doi: 10.1371/journal.pone.0099818 . PMC   4067273 . PMID   24955574.
  16. 1 2 Bruinsma G, Cullen E, Greig NH, Lahiri D, Sambamurti K, Friedhoff L (2006-07-01). "P1-004: Oral treatment of mice with Posiphen™ significantly lowers brain levels of beta amyloid (1-42)". Alzheimer's & Dementia. 2 (3S_Part_4): S95. doi:10.1016/j.jalz.2006.05.379. ISSN   1552-5260. S2CID   54399849.
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