Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease.
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.
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.
Mauro
M
Fà
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.
Hong
H
Zhang
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.
Agnieszka
A
Staniszewski
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.
Faisal
F
Saeed
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.
Li W
LW
Shen
Department of Medicinal and Biological Chemistry, University of Ohio at Toledo, Frederic and Mary Wolfe Center, Toledo, OH, USA.
Isaac T
IT
Schiefer
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
Marton I
MI
Siklos
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
Subhasish
S
Tapadar
Department of Chemistry, McMicken College of Arts & Sciences, University of Cincinnati, Cincinnati, OH, USA.
Vladislav A
VA
Litosh
Department of Pathology, SUNY Downstate Medical Center, Brooklyn, NY, USA.
Jenny
J
Libien
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
Pavel A
PA
Petukhov
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.
Andrew F
AF
Teich
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
Gregory R J
GR
Thatcher
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.
Ottavio
O
Arancio
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects; D006023:Glycoproteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D013049:Spectrin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); C039304:calpain inhibitors; D013049:Spectrin
Alzheimer’s disease; amyloid-β; calpain; learning; long-term potentiation; memory