Dysregulation of cysteine proteases has been implicated in the progression of CNS diseases, such as Alzheimer’s disease. More precisely, it has been posited that the hyperactivation of certain isoforms of cathepsins and calpains, namely calpain-1 and cathepsin B, may initiate neuronal apoptosis in accordance with the “Calpain-Cathepsin hypothesis”. Therefore, targeting these enzymes with small molecule inhibitors may present an effective strategy in impeding the progression of the illness. Our early lead oxirane electrophilic compound, epoxysuccinate NYC-438, has been subjected to a battery of <i>in vitro</i> and <i>in vivo</i> assays. Both NYC-438 and the commercial calpain inhibitor, E-64d, possess significant potency; however, both show limited brain bioavailability and poor selectivity. For these reasons, the objective has been to design and synthesize reversible, selective inhibitors with improved pharmacokinetics. Moreover, we hope to answer whether preferred selective inhibition of one enzyme alone matters. By modifying the early lead NYC-438, a novel series of compounds containing a nitrile warhead were synthesized, some of which showed selective inhibition towards cathepsin K with AJ1-35 and ING-108 being the most potent and selective. In addition, a series of α-ketoamide compounds were synthesized as selective calpain inhibitors. A few compounds from each of the series were then advanced to two different cell-based assays, both showing positive results: neuroprotection against oxygen-glucose deprivation and increased CREB phosphorylation implicated in synaptic plasticity.

Design and synthesis of peptidomimetics with attenuated reactivity for the treatment of neurodegenerative diseases

2019 Spring National Meeting

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