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Project

Validatie van het oxadiazolon isosteer als een carboxylaatvervangende groep in caspase inhibitoren: benaderingen gebaseerd op optimalisatie van Strecker-afgeleide methodologieën en "ontarget" strategieën.

Caspases are intracellular, aspartate selective cysteine proteases. Given their central role in cell death and inflammation, caspases have been studied intensively as drug targets to date. Most attention so far has gone to caspases 1 and 3: these are generally considered to be the prime end-effectors of cellular inflammation and apoptosis pathways, respectively.2 In spite of impressive preclinical results and significant investment in clinical evaluation, no caspase inhibitors have so far been approved as drugs by FDA or EMA. Two important reasons therefore are commonly cited: (1) The large structural homology of caspases that complicates the identification of selective compounds. (2) The limited biopharmaceutical quality of most compounds. Many contain an irreversible covalent warhead function that can potentially induce off-target effects. Most inhibitor families also contain a free carboxylate. Both the ionic character of this group and its potential for toxic metabolite formation, most probably discount critically on the permeability and ADME-Tox properties of inhibitors. Preliminary experiments at UAMC have identified the oxadiazolone moiety as a useful isosteric replacement for the carboxylate group in caspase inhibitors (unpublished data). Research in this proposal will investigate this finding by introducing an oxadiazolone group in several relevant classes of caspase inhibitors. In addition, synthetic methodology based on the Strecker reaction will be elaborated. The latter will allow efficient access to caspase inhibitors with less reactive warhead types. Finally, drug discovery methodology will be developed that should allow "on-target" synthesis of the inhibitor classes that are studied in this proposal.
Datum:1 okt 2016 →  30 sep 2018
Trefwoorden:CHEMISCHE BIOLOGIE, MEDICINALE CHEMIE
Disciplines:Ontdekking en evaluatie van biomarkers, Ontdekking en evaluatie van geneesmiddelen, Medicinale producten, Farmaceutica, Farmacognosie en fytochemie, Farmacologie, Farmacotherapie, Toxicologie en toxinologie, Andere farmaceutische wetenschappen
Project type:Samenwerkingsproject