Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer’s Disease

Article type: Research Article

Authors: Fà, Mauro^a | Zhang, Hong^a | Staniszewski, Agnieszka^a | Saeed, Faisal^a | Shen, Li W.^a | Schiefer, Isaac T.^b | Siklos, Marton I.^c | Tapadar, Subhasish^c | Litosh, Vladislav A.^d | Libien, Jenny^e | Petukhov, Pavel A.^c | Teich, Andrew F.^a | Thatcher, Gregory R.J.^c | Arancio, Ottavio^{a; *}

Affiliations: [a] Department of Pathology and Cell Biology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA | [b] Department of Medicinal and Biological Chemistry, University of Ohio at Toledo, Frederic and Mary Wolfe Center, Toledo, OH, USA | [c] Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA | [d] Department of Chemistry, McMicken College of Arts & Sciences, University of Cincinnati, Cincinnati, OH, USA | [e] Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY, USA

Correspondence: [*] Correspondence to: Ottavio Arancio, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, 630W 168th Street, New York, NY 10032, USA. Tel.: +1 212 342 0533; E-mail: [email protected]

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-β 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.

Keywords: Alzheimer’s disease, amyloid-β, calpain, learning, long-term potentiation, memory

DOI: 10.3233/JAD-150618

Journal: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 707-721, 2016