Dihexa

Last updated
Dihexa
Dihexa.svg
Clinical data
Other namesN-(1-Oxohexyl)-l-tyrosyl-N-(6-amino-6-oxohexyl)-l-isoleucinamide
Identifiers
  • 6-[(2S,3S)-2-[(2S)-2-hexanamido-3-(4-hydroxyphenyl)propanamido]-3-methylpentanamido]hexanamide
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C27H44N4O5
Molar mass 504.672 g·mol−1
3D model (JSmol)
  • CCCCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCCCCCC(N)=O
  • InChI=1S/C27H44N4O5/c1-4-6-8-12-24(34)30-22(18-20-13-15-21(32)16-14-20)26(35)31-25(19(3)5-2)27(36)29-17-10-7-9-11-23(28)33/h13-16,19,22,25,32H,4-12,17-18H2,1-3H3,(H2,28,33)(H,29,36)(H,30,34)(H,31,35)/t19-,22-,25-/m0/s1
  • Key:XEUVNVNAVKZSPT-JTJYXVOQSA-N

Dihexa (developmental code PNB-0408; also known as N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is an oligopeptide drug derived from angiotensin IV that binds with high affinity to hepatocyte growth factor (HGF) and potentiates its activity at its receptor, c-Met. [1] [2] The compound has been found to potently improve cognitive function in animal models of Alzheimer's disease-like mental impairment. [3] [4] [5] [6] [7] [8] [9] [10] [11] In an assay of neurotrophic activity, dihexa was found to be seven orders of magnitude more potent than brain-derived neurotrophic factor. [12]

According to a patent, "Short duration safety studies with dihexa have uncovered no apparent toxicity. Of particular note is a lack of neoplastic induction [ citation needed ], since c-Met is recognized as an oncogene. This is unsurprising since oncogenesis requires multiple mutations including both oncogene induction and tumor suppressor attenuation." [13] [ citation needed ]

History

Dihexa was developed by Joseph Harding and his team at Washington State University. [14] Later developments were done by M3 Biotechnology, a company founded to commercialize dihexa. [15]

Fosgonimeton, a phosphate pro-drug of dihexa is currently in clinical trials for the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's disease [16]

References

  1. ↑ Wright JW, Harding JW. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease. J Alzheimers Dis. 2015;45(4):985-1000. doi : 10.3233/JAD-142814 PMID   25649658
  2. ↑ Wright JW, Kawas LH, Harding JW. The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases. Prog Neurobiol 2015 Feb;125:26-46. doi : 10.1016/j.pneurobio.2014.11.004 PMID   25455861
  3. ↑ US 8598118,Harding JW, Wright JW, Benoist CC, Kawas LH, Wayman GA,"Hepatocyte growth factor mimics as therapeutic agents",issued 3 December 2013
  4. ↑ Benoist CC, Wright JW, Zhu M, Appleyard SM, Wayman GA, Harding JW (October 2011). "Facilitation of hippocampal synaptogenesis and spatial memory by C-terminal truncated Nle1-angiotensin IV analogs". The Journal of Pharmacology and Experimental Therapeutics. 339 (1): 35–44. doi:10.1124/jpet.111.182220. PMC   3186286 . PMID   21719467.
  5. ↑ Uribe PM, Kawas LH, Harding JW, Coffin AB (January 2015). "Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure". Frontiers in Cellular Neuroscience. 9 (3): 3. doi: 10.3389/fncel.2015.00003 . PMC   4309183 . PMID   25674052.
  6. ↑ Wright JW, Harding JW (January 2015). "The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease". Journal of Alzheimer's Disease. 45 (4): 985–1000. doi:10.3233/JAD-142814. PMID   25649658.
  7. ↑ Siller R, Greenhough S, Naumovska E, Sullivan GJ (May 2015). "Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells". Stem Cell Reports. 4 (5): 939–952. doi:10.1016/j.stemcr.2015.04.001. PMC   4437467 . PMID   25937370.
  8. ↑ "32. The Innovators: Designing Medicine's Holy Grail". KOMO News. 27 August 2015. Retrieved 11 October 2015.
  9. ↑ "Brain Connections in Alzheimer's Rebuilt with New Peptide". GEN News Highlights. 11 October 2015. Retrieved 11 October 2015.
  10. ↑ "Brain-Enhancing 'Smart Drugs' Are Going Commercial". VICE. 17 July 2014. Retrieved 11 October 2015.
  11. ↑ Ho JK, Nation DA. Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies. Neurosci Biobehav Rev. 2018 Sep;92:209-225. doi : 10.1016/j.neubiorev.2018.05.005 PMID   29733881
  12. ↑ "Prospective Alzheimer's drug builds new brain cell connections, improves cognitive function of rats". ScienceDaily. 11 October 2012. Retrieved 11 October 2015.
  13. ↑ USpatent 0337024,Allison Coffin, Joseph Harding, Leen Kawas, Phillip Uribe,"Novel Lead Compound for Otoprotection: Targeting HGF Signaling with Dihexa",issued 2015-11-26
  14. ↑ "Dihexa" (PDF). Alzheimer's Drug Discovery Foundation. August 13, 2021.
  15. ↑ "Fosgonimeton | ALZFORUM". www.alzforum.org. Retrieved 2023-04-20.
  16. ↑ "Fosgonimeton - Athira Pharma". AdisInsight. Springer Nature Switzerland AG.
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