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Design and Synthesis of a New Non-Covalent Caspase-3 Inhibitor with Neuroprotective Property
* 1 , 2 , 1 , 3 , 4 , 5 , 6 , 6 , 7 , 2, 8
1  Istituto di Chimica Biomolecolare - CNR, Italy
2  Department of Drug Design, University of Groningen, Groningen, The Netherlands
3  Istituto di Chimica Biomolecolare - Consiglio Nazionale delle Ricerche, Italy
4  Istituto di Farmacologia Traslazionale - Consiglio Nazionale delle Ricerche, Italy
5  Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands
6  Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen
7  Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University
8  Palackӯ University, CATRIN, Department of Innovative Chemistry, Olomouc – Holice, Czech Republic;
Academic Editor: Alfredo Berzal-Herranz (registering DOI)

Caspases, the family of cysteine aspartate specific proteases, are well known as killer enzymes driving cell death via apoptosis or pyroptosis. However, the latest findings on the caspases indicate important and non-lethal roles of these enzymes ranging from immune response, cell fate determination, cell proliferation and cellular remodeling. Caspase-3 is a key mediator of neuronal programmed cell death and plays an essential role in the development of the nervous system. Its activation is a feature of many chronic neurodegenerative diseases often characterized by perturbations in physiological synapses structure and function as in Alzheimer and Parkinson diseases. Therefore, these studies validate caspase-3 inhibitors as a novel pharmacological target against multiple diseases.

Many caspase-3 inhibitors have been developed but only few compounds have progressed in clinical trials. Novel, improved, brain penetrable compounds are urgently needed for developing new therapeutics for neurodegenerative pathologies. We have designed and synthesized via multicomponent reaction (MCR) a new non-covalent, non-peptidomimetic, and selective caspase-3 inhibitor.

The results of the biological tests performed on the compound ALC-129 highlighted inhibitory activity on Caspase-3, selectivity with respect to Caspase-1, and potential neuroprotective activity for glutamate-induced toxicity (oxytosis). Labelled compound 11C-ALC-129 has been prepared for Positron Emission Tomography (PET) preliminary studies.

Keywords: Caspase-3 inhibitor, neuroprotective activity