ALTO-100

ALTO-100
Clinical data
Other namesNSI-189; NeuralStem Inc 189
Routes of
administration		By mouth[1]
Drug classHippocampal neurogenesis/neuroplasticity stimulant; Indirect brain-derived neurotrophic factor modulators[2]
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Elimination half-life17.4–20.5 hours[1]
Identifiers
  • (4-Benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC22H30N4O
Molar mass366.509 g·mol−1
3D model (JSmol)
  • CC(C)CCNC1=C(C=CC=N1)C(=O)N2CCN(CC2)CC3=CC=CC=C3
  • InChI=1S/C22H30N4O/c1-18(2)10-12-24-21-20(9-6-11-23-21)22(27)26-15-13-25(14-16-26)17-19-7-4-3-5-8-19/h3-9,11,18H,10,12-17H2,1-2H3,(H,23,24)
  • Key:DYTOQURYRYYNOR-UHFFFAOYSA-N ☒N

ALTO-100, previously known as NSI-189 (NeuralStem Inc. 189),[3] is a drug described as a hippocampal neurogenesis stimulant and indirect brain-derived neurotrophic factor (BDNF) modulator which is under development for the treatment of major depressive disorder (MDD), bipolar depression, and post-traumatic stress disorder (PTSD).[4][5][6][7][8] There has also been interest in ALTO-100 for possible treatment of cognitive impairment and neurodegeneration.[9][10][11] It is taken by mouth.[1]

ALTO-100's exact mechanism of action is unknown.[3][6][7] However, it is thought to work through indirectly enhancing BDNF signaling and increasing neuroplasticity and neurogenesis in the hippocampus.[11][12][13][14] The drug dose-dependently increases hippocampal volume at sufficiently high doses in rodents.[1][12] However, it did not significantly affect hippocampal volume in humans in a clinical study.[1] ALTO-100 is a first-in-class drug and a small molecule.[2]

As of July 2024, ALTO-100 is in phase 2 clinical trials for MDD, bipolar depression, and PTSD.[4] A phase 3 trial for MDD is being planned.[4] Findings of the effectiveness of ALTO-100 in treating MDD in phase 1 and 2 trials have been mixed, although cognitive and memory improvements have been observed.[15][16][17][18][5][4] ALTO-100 is under development by Alto Neuroscience[4][8] and was previously under development by Neuralstem, Inc.[5][19]

  1. ^ a b c d e Cite error: The named reference McIntyreJoheRong2017 was invoked but never defined (see the help page).
  2. ^ a b "Alto Neuroscience Receives Funding Award from Wellcome Trust to Accelerate Development of ALTO-100 in Bipolar Depression Leveraging Precision Psychiatry Approach". Nasdaq. 5 April 2024. Retrieved 5 August 2024.
  3. ^ a b Cite error: The named reference Osborne2024 was invoked but never defined (see the help page).
  4. ^ a b c d e "ALTO 100". AdisInsight. Springer Nature Switzerland AG. 29 July 2024. Retrieved 5 August 2024.
  5. ^ a b c "NSI 189". AdisInsight. Springer Nature Switzerland AG. 28 September 2022. Retrieved 5 August 2024.
  6. ^ a b Dejanovic B, Sheng M, Hanson JE (January 2024). "Targeting synapse function and loss for treatment of neurodegenerative diseases". Nat Rev Drug Discov. 23 (1): 23–42. doi:10.1038/s41573-023-00823-1. PMID 38012296.
  7. ^ a b Singewald N, Sartori SB, Reif A, Holmes A (March 2023). "Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder". Neuropharmacology. 226: 109418. doi:10.1016/j.neuropharm.2023.109418. PMC 10372846. PMID 36623804.
  8. ^ a b Brady LS, Lisanby SH, Gordon JA (2023). "New directions in psychiatric drug development: promising therapeutics in the pipeline". Expert Opin Drug Discov. 18 (8): 835–850. doi:10.1080/17460441.2023.2224555. PMID 37352473.
  9. ^ Bouhassira EE (15 June 2015). The SAGE Encyclopedia of Stem Cell Research. SAGE Publications. pp. 843–. ISBN 978-1-4833-4767-7.
  10. ^ Fava M, Johe K, Ereshefsky L, Gertsik LG, English BA, Bilello JA, et al. (October 2016). "A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients". Molecular Psychiatry. 21 (10): 1372–1380. doi:10.1038/mp.2015.178. PMC 5030464. PMID 26643541. The brains of treated mice showed significantly increased neurogenesis in the dentate gyrus and significantly increased hippocampal volume (Data on file, Neuralstem, non-peer-reviewed). NSI-189 is believed to have a highly specific effect in the hippocampus and subventricular zone, the two well-known neurogenic regions in adult central nervous system, and nowhere else in the central nervous system (Data on file, Neuralstem, nonpeer-reviewed).
  11. ^ a b Neuralstem (March 2016), Neuralstem Inc. March 2016 Corporate Presentation (PDF), retrieved 25 March 2016[dead link] Alt URL
  12. ^ a b Cite error: The named reference Alto2024 was invoked but never defined (see the help page).
  13. ^ Cite error: The named reference SEC2024a was invoked but never defined (see the help page).
  14. ^ Cite error: The named reference Anderson2023 was invoked but never defined (see the help page).
  15. ^ Cite error: The named reference BeckervordersandforthRolando2020 was invoked but never defined (see the help page).
  16. ^ McNerlin C, Guan F, Bronk L, Lei K, Grosshans D, Young DW, et al. (November 2022). "Targeting hippocampal neurogenesis to protect astronauts' cognition and mood from decline due to space radiation effects". Life Sci Space Res (Amst). 35: 170–179. doi:10.1016/j.lssr.2022.07.007. PMID 36336363. [NSI-189] progressed to Phase-II clinical trials for evaluation of its effects on mitigating depression (Papakostas et al., 2020). Although the drug was well tolerated over 12 weeks at daily doses of either 40 or 80 mg, the primary endpoints for the clinical trial were not met. Interestingly however, cognitive benefits were noted at 40 mg, which included response accuracy on executive function testing mental flexibility, response speed on a measure of choice reaction time, and accuracy on a measure of delayed recall for symbol digit paired associates (Johe et al., 2020). The failure of the NSI-189 to get FDA approval for use in MDD and/or cognitive decline highlights the need for development of drugs based on specific targets and not phenotypic screens.
  17. ^ Dhir A (January 2017). "Investigational drugs for treating major depressive disorder". Expert Opin Investig Drugs. 26 (1): 9–24. doi:10.1080/13543784.2017.1267727. PMID 27960559.
  18. ^ Cite error: The named reference PapakostasJoheHand2020 was invoked but never defined (see the help page).
  19. ^ Cite error: The named reference SEC2024b was invoked but never defined (see the help page).