Structure-activity relationship studies of functionalized aromatic peptidomimetics as neurolysin activators

Md Shafikur Rahman, Shiva Hadi Esfahani, Saeideh Nozohouri, Shikha Kumari, Joanna Kocot, Yong Zhang, Thomas J. Abbruscato, Vardan T. Karamyan, Paul C. Trippier

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Modulating peptidase neurolysin (Nln) has been identified as a potential cerebroprotective target for the development of therapeutics for ischemic stroke. Continued structure–activity relationship studies on peptidomimetic small molecule activators of Nln bearing electron-donating and electron- withdrawing functionalized phenyls are explored. Incorporation of fluorine or trifluoromethyl groups produces Nln activators with enhanced A50, while methoxy substitution produces derivatives with enhanced Amax. Selected activators containing methoxy or trifluoromethyl substitution are selective for Nln over related peptidases and possess increased blood–brain barrier penetrability than initial hits.

Original languageEnglish (US)
Article number128669
JournalBioorganic and Medicinal Chemistry Letters
StatePublished - May 15 2022


  • Blood–brain barrier
  • Electron-donating
  • Electron-withdrawing
  • Neurolysin activators
  • Peptidases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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