Novel selective calpain 1 inhibitors as potential therapeutics in alzheimer's disease

Mauro Fa, Hong Zhang, Agnieszka Staniszewski, Faisal Saeed, Li W. Shen, Isaac T. Schiefer, Marton I. Siklos, Subhasish Tapadar, Vladislav A. Litosh, Jenny Libien, Pavel A. Petukhov, Andrew F. Teich, Gregory R.J. Thatcher, Ottavio Arancio

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Alzheimer's disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid-β, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer's disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid Elevation. However, molecules currently available as effective calpain inhibitors lack adequate selectivity. This work is aimed at characterizing the efficacy of a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against the disease.

Original languageEnglish (US)
Pages (from-to)707-721
Number of pages15
JournalJournal of Alzheimer's Disease
Volume49
Issue number3
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • Calpain
  • Learning
  • Long-term potentiation
  • Memory

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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