Discovery of Neurolysin Activators with Preclinical Efficacy in an Ischemic Stroke Model

The peptidase neurolysin (Nln) is upregulated following ischemic stroke to activate endogenous cerebroprotective mechanisms and has subsequently emerged as a therapeutic target for drug discovery efforts. Overexpression of Nln in a mouse model of ischemic stroke results in significant improvement of stroke outcomes. Herein, we report the discovery of the first non-peptide Nln activators based around a central pyridine-piperazine scaffold that possesses nanomolar potency. This scaffold, exemplified by compounds 7c and 7g, exhibits greater in vitro half-life, blood−brain barrier penetration, mouse brain and mouse plasma stability than previously reported peptidomimetic Nln activators. Compound 7g afforded an in vivo protective effect in the MCAO mouse model of ischemic stroke, significantly reducing infarct volume and brain water content, marking the first report of a small molecule Nln activator with in vivo cerebroprotective effects in a preclinical model.