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

Bioorg Med Chem Lett. 2022 May 15:64:128669. doi: 10.1016/j.bmcl.2022.128669. Epub 2022 Mar 12.

Abstract

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.

Keywords: Blood–brain barrier; Electron-donating; Electron-withdrawing; Neurolysin activators; Peptidases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Metalloendopeptidases / metabolism
  • Peptide Hydrolases / metabolism
  • Peptidomimetics* / pharmacology
  • Structure-Activity Relationship

Substances

  • Peptidomimetics
  • Peptide Hydrolases
  • Metalloendopeptidases
  • neurolysin