biostudies-literatureRahman MSUniversity of Nebraska Medical CenterTexas Tech UniversityNINDS NIH HHSNational Institutes of Health128669https://www.ebi.ac.uk/biostudies/studies/S-EPMC8985228biostudies-literatureUnknown64Modulating 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 A_max. Selected activators containing methoxy or trifluoromethyl substitution are selective for Nln over related peptidases and possess increased blood-brain barrier penetrability than initial hits.Bioorganic & medicinal chemistry lettersStructure-activity relationship studies of functionalized aromatic peptidomimetics as neurolysin activators.PMC8985228R01NS106879R01 NS106879Kumari SZhang YTrippier PCAbbruscato TJRahman MSKocot JKaramyan VTEsfahani SHNozohouri SfalseStructure-activity relationship studies of functionalized aromatic peptidomimetics as neurolysin activators.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 A_max. Selected activators containing methoxy or trifluoromethyl substitution are selective for Nln over related peptidases and possess increased blood-brain barrier penetrability than initial hits.2022-01-01T00:00:00Z2022 May2025-04-27T04:04:58.82Z2025-04-06T19:08:39.823ZS-EPMC89852283529234310.1016/j.bmcl.2022.128669