Stroke is the world's second most common cause of death and disability. Ischemic stroke (IS), a primary subtype of stroke, has ineffective and limited treatment options, resulting in a large unmet medical need for novel therapies. Endopeptidase neurolysin (Nln) has been identified as one of the brain's self-protective components in recent investigations, and it plays a key role in the maintenance and recovery of normal brain functions after IS. The development of therapeutic compounds that can trigger the brain's self-protective/repair mechanism after IS will require a better understanding of these processes. The ability of Nln to deactivate multiple neurotoxins and create at least three cerebro-protective neuropeptides is one of its most important functions in the post-IS brain. In an effort to discover potent drug-like Nln activators, over eighty molecules have been synthesized and evaluated as Nln activators, seventeen of which have shown activity at low micromolar concentrations, five of which are significantly stable in mouse plasma and brain, and five of which are brain permeable and selective to neurolysin over similar peptidases. Further lead optimization is ongoing to develop highly potent, brain-permeable, stable, and selective Nln activators. We aim to generate very effective, brain-permeable 'drug-like' small molecule activators of Nln, which would be used as potential leads for developing therapies to treat IS.

Synthesis, and evaluation of peptidase neurolysin activators to treat ischemic stroke

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