 | |
| Clinical data | |
|---|---|
| Trade names | Posiphen, ANVS-401 |
|
Routes of administration | By mouth |
| Legal status | |
| Legal status |
|
| Identifiers | |
| |
| PubChem CID | |
| ChemSpider | |
| ChEMBL | |
| CompTox Dashboard ( EPA) | |
| Chemical and physical data | |
| Formula | C20H23N3O2 |
| Molar mass | 337.423 g·mol−1 |
| 3D model ( JSmol) | |
| |
| |
Buntanetap is an orally-administered small molecule inhibitor of several neurotoxic proteins that is under investigation in the treatment of Alzheimer's disease, frontotemporal dementia, chronic traumatic encephalopathy and Parkinson's disease. [1] [2] It is the (+) enantiomer of phenserine, as the (-) enantiomer also has unwanted anticholinergic effects. [3] It is currently in phase III trials for the treatment of Parkinson's. [4]
Although the ongoing clinical trials yet have affirmed if buntanetap can be pursued as a novel Alzheimer's disease's treatment, buntanetap has demonstrated its potential by impeding neurodegenerative mechanisms. Buntanetap performs in a noncholinergic manner, including but not limited to, the suppressing action on APP translation [5] and β-secretase Activity. [6] [7] The β-secretase Activity is instigated by the accumulation of Aβ peptides which are augmented along with aging of the human brain. [8] In clinical demonstrations with brain cell-lines, two contrasting forms showed the noncholinergic mechanism to an equal extent, with respect to their potency and efficacy. [9] [10]
Buntanetap is relatively well tolerated with the administration of doses, even higher than the maximally tolerable dose of (-)-phenserine. In vivo, the levels of APP protein in the cortex were reduced by buntanetap with an ED50 of ???(median Effective Dose). [9] [11] 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. [12] Once buntanetap is dosed over 160 mg, gastro-intestinal related symptoms including nausea and vomiting, were manifested. [12] The drug additionally presents the rapid absorption rate, occurred within an hour or two. Pharmacokinetics of buntanetap was overall kept linear.
- ^ Gubar M (11 January 2022). "Buntanetap: Breakthrough in Treatment of Alzheimer's and Parkinson's • BioPharma Media". BioPharma Media. Retrieved 13 January 2023.
- ^ "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.
- ^ 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.
- ^ "A 6-month Prospective, Randomized, Double-blind, Placebo-controlled Clinical Trial Investigating the Efficacy, Safety, and Tolerability of Two Different Doses of Buntanetap or Placebo in Patients With Early Parkinson's Disease". clinicaltrials.gov. 5 January 2023. Retrieved 13 January 2023.
- ^ Bandyopadhyay S, Rogers JT (April 2014). "Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis". Biochemical Pharmacology. Alzheimer's Disease – Amyloid, Tau and Beyond. 88 (4): 486–494. doi: 10.1016/j.bcp.2014.01.032. PMC 4064675. PMID 24513321.
- ^ Maccecchini ML, Chang MY, Pan C, John V, Zetterberg H, Greig NH (September 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. doi: 10.1136/jnnp-2012-302589. PMC 3415310. PMID 22791904.
- ^ Teich AF, Sharma E, Barnwell E, Zhang H, Staniszewski A, Utsuki T, et al. (2018-01-17). "Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse". Alzheimer's & Dementia. 4 (1): 37–45. doi: 10.1016/j.trci.2017.12.001. PMC 6021259. PMID 29955650.
- ^ Pan X, Green BD (January 2019). "Temporal Effects of Neuron-specific beta-secretase 1 (BACE1) Knock-in on the Mouse Brain Metabolome: Implications for Alzheimer's Disease". Neuroscience. 397: 138–146. doi: 10.1016/j.neuroscience.2018.11.031. PMID 30496823. S2CID 53721607.
- ^ a b 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.
- ^ Lahiri DK, Chen D, Maloney B, Holloway HW, Yu QS, Utsuki T, et al. (January 2007). "The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice". The Journal of Pharmacology and Experimental Therapeutics. 320 (1): 386–396. doi: 10.1124/jpet.106.112102. PMID 17003227. S2CID 25507424.
- ^ 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.
- ^ a b 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.
|
| |
| Clinical data | |
|---|---|
| Trade names | Posiphen, ANVS-401 |
|
Routes of administration | By mouth |
| Legal status | |
| Legal status |
|
| Identifiers | |
| |
| PubChem CID | |
| ChemSpider | |
| ChEMBL | |
| CompTox Dashboard ( EPA) | |
| Chemical and physical data | |
| Formula | C20H23N3O2 |
| Molar mass | 337.423 g·mol−1 |
| 3D model ( JSmol) | |
| |
| |
Buntanetap is an orally-administered small molecule inhibitor of several neurotoxic proteins that is under investigation in the treatment of Alzheimer's disease, frontotemporal dementia, chronic traumatic encephalopathy and Parkinson's disease. [1] [2] It is the (+) enantiomer of phenserine, as the (-) enantiomer also has unwanted anticholinergic effects. [3] It is currently in phase III trials for the treatment of Parkinson's. [4]
Although the ongoing clinical trials yet have affirmed if buntanetap can be pursued as a novel Alzheimer's disease's treatment, buntanetap has demonstrated its potential by impeding neurodegenerative mechanisms. Buntanetap performs in a noncholinergic manner, including but not limited to, the suppressing action on APP translation [5] and β-secretase Activity. [6] [7] The β-secretase Activity is instigated by the accumulation of Aβ peptides which are augmented along with aging of the human brain. [8] In clinical demonstrations with brain cell-lines, two contrasting forms showed the noncholinergic mechanism to an equal extent, with respect to their potency and efficacy. [9] [10]
Buntanetap is relatively well tolerated with the administration of doses, even higher than the maximally tolerable dose of (-)-phenserine. In vivo, the levels of APP protein in the cortex were reduced by buntanetap with an ED50 of ???(median Effective Dose). [9] [11] 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. [12] Once buntanetap is dosed over 160 mg, gastro-intestinal related symptoms including nausea and vomiting, were manifested. [12] The drug additionally presents the rapid absorption rate, occurred within an hour or two. Pharmacokinetics of buntanetap was overall kept linear.
- ^ Gubar M (11 January 2022). "Buntanetap: Breakthrough in Treatment of Alzheimer's and Parkinson's • BioPharma Media". BioPharma Media. Retrieved 13 January 2023.
- ^ "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.
- ^ 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.
- ^ "A 6-month Prospective, Randomized, Double-blind, Placebo-controlled Clinical Trial Investigating the Efficacy, Safety, and Tolerability of Two Different Doses of Buntanetap or Placebo in Patients With Early Parkinson's Disease". clinicaltrials.gov. 5 January 2023. Retrieved 13 January 2023.
- ^ Bandyopadhyay S, Rogers JT (April 2014). "Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis". Biochemical Pharmacology. Alzheimer's Disease – Amyloid, Tau and Beyond. 88 (4): 486–494. doi: 10.1016/j.bcp.2014.01.032. PMC 4064675. PMID 24513321.
- ^ Maccecchini ML, Chang MY, Pan C, John V, Zetterberg H, Greig NH (September 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. doi: 10.1136/jnnp-2012-302589. PMC 3415310. PMID 22791904.
- ^ Teich AF, Sharma E, Barnwell E, Zhang H, Staniszewski A, Utsuki T, et al. (2018-01-17). "Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse". Alzheimer's & Dementia. 4 (1): 37–45. doi: 10.1016/j.trci.2017.12.001. PMC 6021259. PMID 29955650.
- ^ Pan X, Green BD (January 2019). "Temporal Effects of Neuron-specific beta-secretase 1 (BACE1) Knock-in on the Mouse Brain Metabolome: Implications for Alzheimer's Disease". Neuroscience. 397: 138–146. doi: 10.1016/j.neuroscience.2018.11.031. PMID 30496823. S2CID 53721607.
- ^ a b 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.
- ^ Lahiri DK, Chen D, Maloney B, Holloway HW, Yu QS, Utsuki T, et al. (January 2007). "The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice". The Journal of Pharmacology and Experimental Therapeutics. 320 (1): 386–396. doi: 10.1124/jpet.106.112102. PMID 17003227. S2CID 25507424.
- ^ 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.
- ^ a b 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.