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

doi:10.1016/j.bmcl.2022.128669

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 journal › Article › peer-review

1 Scopus citations

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 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.

Original language	English (US)
Article number	128669
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	64
DOIs	https://doi.org/10.1016/j.bmcl.2022.128669
State	Published - May 15 2022

Keywords

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

Access to Document

10.1016/j.bmcl.2022.128669

Cite this

@article{24619b28c8d54a34b2593083825cc122,

title = "Structure-activity relationship studies of functionalized aromatic peptidomimetics as neurolysin activators",

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",

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

note = "Funding Information: This project was supported by NIH grant R01NS106879 to P.C.T., V.T.K. and T.J.A. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Additional support was provided by the University of Nebraska Medical Center and Texas Tech University Health Sciences Center School of Pharmacy. Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

year = "2022",

month = may,

day = "15",

doi = "10.1016/j.bmcl.2022.128669",

language = "English (US)",

volume = "64",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Structure-activity relationship studies of functionalized aromatic peptidomimetics as neurolysin activators

AU - Rahman, Md Shafikur

AU - Esfahani, Shiva Hadi

AU - Nozohouri, Saeideh

AU - Kumari, Shikha

AU - Kocot, Joanna

AU - Zhang, Yong

AU - Abbruscato, Thomas J.

AU - Karamyan, Vardan T.

AU - Trippier, Paul C.

N1 - Funding Information: This project was supported by NIH grant R01NS106879 to P.C.T., V.T.K. and T.J.A. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Additional support was provided by the University of Nebraska Medical Center and Texas Tech University Health Sciences Center School of Pharmacy. Publisher Copyright: © 2022 Elsevier Ltd

PY - 2022/5/15

Y1 - 2022/5/15

N2 - 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.

AB - 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.

KW - Blood–brain barrier

KW - Electron-donating

KW - Electron-withdrawing

KW - Neurolysin activators

KW - Peptidases

UR - http://www.scopus.com/inward/record.url?scp=85126578328&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85126578328&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2022.128669

DO - 10.1016/j.bmcl.2022.128669

M3 - Article

C2 - 35292343

AN - SCOPUS:85126578328

SN - 0960-894X

VL - 64

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

M1 - 128669

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this