ArticleJournal of medicinal chemistry2021
Discovery of First-in-Class Peptidomimetic Neurolysin Activators Possessing Enhanced Brain Penetration and Stability.
Article in Journal of medicinal chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Structural and functional dissection of human neurolysin through alanine-scanning mutagenesis.The FEBS journal · 2026Article
- Discovery of a pyridine-piperazine-based small molecule that enhances the activity of peptidase neurolysin.The Journal of pharmacology and experimental therapeutics · 2026Article
- Conformation Driven Enhancement of Neurolysin Activity in Presence of a Small Molecule Activator.bioRxiv : the preprint server for biology · 2026Article
- The Missing Enzymes: A Call to Update Pharmacological Profiling Practices for Better Drug Safety Assessment.Journal of medicinal chemistry · 2025Review
- Structural basis of divergent substrate recognition and inhibition of human neurolysin.Scientific reports · 2024Article
- Imidazole Bioisostere Activators of Endopeptidase Neurolysin with Enhanced Potency and Metabolic Stability.ACS medicinal chemistry letters · 2024Article
- The evolution of small molecule enzyme activators.RSC medicinal chemistry · 2023Review
- Discovery of the Next Generation of Non-peptidomimetic Neurolysin Activators with High Blood-Brain Barrier Permeability: a Pharmacokinetics Study in Healthy and Stroke Animals.Pharmaceutical research · 2023Article
- Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands.European journal of medicinal chemistry · 2023Article
- Permeability of Metformin across an In Vitro Blood-Brain Barrier Model during Normoxia and Oxygen-Glucose Deprivation Conditions: Role of Organic Cation Transporters (Octs).Pharmaceutics · 2023Article
- Is Diminazene an Angiotensin-Converting Enzyme 2 (ACE2) Activator? Experimental Evidence and Implications.The Journal of pharmacology and experimental therapeutics · 2022Article
- Structure-activity relationship studies of functionalized aromatic peptidomimetics as neurolysin activators.Bioorganic & medicinal chemistry letters · 2022Article
- Small molecule neurolysin activators, potential multi-mechanism agents for ischemic stroke therapy.Expert opinion on therapeutic targets · 2022Article
- Identification and Characterization of Two Structurally Related Dipeptides that Enhance Catalytic Efficiency of Neurolysin.The Journal of pharmacology and experimental therapeutics · 2021Article
Corrections and comments
- Erratum issued
Authors and funding
12 authors.
Funding
Abstract
Peptidase neurolysin (Nln) is an enzyme that functions to cleave various neuropeptides. Upregulation of Nln after stroke has identified the enzyme as a critical endogenous cerebroprotective mechanism and validated target for the treatment of ischemic stroke. Overexpression of Nln in a mouse model of stroke results in dramatic improvement of stroke outcomes, while pharmacological inhibition aggravates them. Activation of Nln has therefore emerged as an intriguing target for drug discovery efforts for ischemic stroke. Herein, we report the discovery and hit-to-lead optimization of first-in-class Nln activators based on histidine-containing dipeptide hits identified from a virtual screen. Adopting a peptidomimetic approach provided lead compounds that retain the pharmacophoric histidine moiety and possess single-digit micromolar potency over 40-fold greater than the hit scaffolds. These compounds exhibit 5-fold increased brain penetration, significant selectivity over highly homologous peptidases, greater than 65-fold increase in mouse brain stability, and 'drug-like' fraction unbound in the brain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.