Imidazole Bioisostere Activators of Endopeptidase Neurolysin with Enhanced Potency and Metabolic Stability

Md Shafikur Rahman, Shiva Hadi Esfahani, Yong Zhang, Aarfa Queen, Manar Aljarrah, Haya Kandil, Andrew Baez, Thomas J. Abbruscato, Vardan T. Karamyan, Paul C. Trippier

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The peptidase neurolysin (Nln) has been validated as a potential target for developing therapeutics for ischemic stroke (IS). Overexpression of Nln in a mouse model of IS provides significant cerebroprotection, leading to reduced infarction size and edema volume. Pharmacological inhibition of Nln in the post-stroke brain worsens neurological outcomes. A virtual screen identified dipeptide small-molecule activators of Nln. Optimization studies resulted in a class of peptidomimetic compounds with promising activity. However, these compounds still possessed an amide bond that compromised their stability in plasma and the brain. Herein, we report the synthesis and characterization of a series of amide bioisosteres based on our peptidomimetic leads. Imidazole-based bioisosteres afford scaffolds with increased potency to activate Nln combined with enhanced mouse plasma stability and significantly better brain permeability over the original dipeptide hits.

Original languageEnglish (US)
Pages (from-to)510-517
Number of pages8
JournalACS Medicinal Chemistry Letters
Volume15
Issue number4
DOIs
StatePublished - Apr 11 2024

Keywords

  • Bioisosteres
  • Enzyme activator
  • Ischemic stroke
  • Neurolysin

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Imidazole Bioisostere Activators of Endopeptidase Neurolysin with Enhanced Potency and Metabolic Stability'. Together they form a unique fingerprint.

Cite this