Discovery of a Pyridine-Piperazine-Based Small Molecule That Enhances the Activity of Peptidase Neurolysin
Document Type
Article
Publication Date
3-1-2026
Publication Title
The Journal of Pharmacology and Experimental Therapeutics
Abstract
Neurolysin (Nln) is a peptidase recognized for its cerebroprotective function in acute ischemic stroke. This study aimed to identify small molecule activators of Nln as research tools to further explore the role of this enzyme in stroke and other neurological disorders. Building on our previous computational screen of ∼140,000 compounds from the National Cancer Institute Developmental Therapeutics Program database, we extended experimental testing to the top 100 candidates using an Nln enzymatic assay. A pyridine-piperazine derivative (Py-Pip) was identified as a hit molecule and was characterized in detail. Py-Pip concentration-dependently enhanced the hydrolysis of both synthetic and natural substrates (neurotensin, angiotensin I, and bradykinin) by rat Nln, and displayed comparable activating effects on human and mouse orthologs. Importantly, Py-Pip exhibited a favorable selectivity profile, showing no potentiation of homologous metallopeptidases or unrelated enzymes. Kinetic analysis revealed that Py-Pip increases the catalytic efficiency (V
Volume
393
Issue
3
First Page
103827
Last Page
103827
Recommended Citation
ElSayed ElZorkany H, Kandil H, Jayaraman S, et al. Discovery of a pyridine-piperazine-based small molecule that enhances the activity of peptidase neurolysin. J Pharmacol Exp Ther. 2026;393(3):103827. doi:10.1016/j.jpet.2026.103827
DOI
10.1016/j.jpet.2026.103827
ISSN
1521-0103
PubMed ID
41759240