TY - JOUR
T1 - Discovery of First-in-Class Peptidomimetic Neurolysin Activators Possessing Enhanced Brain Penetration and Stability
AU - Rahman, Md Shafikur
AU - Kumari, Shikha
AU - Esfahani, Shiva Hadi
AU - Nozohouri, Saeideh
AU - Jayaraman, Srinidhi
AU - Kinarivala, Nihar
AU - Kocot, Joanna
AU - Baez, Andrew
AU - Farris, Delaney
AU - Abbruscato, Thomas J.
AU - Karamyan, Vardan T.
AU - Trippier, Paul C.
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/9/9
Y1 - 2021/9/9
N2 - Peptidase neurolysin (Nln) is an enzyme that functions to cleave various neuropeptides. Upregulation of Nln after stroke has identified the enzyme as a critical endogenous cerebroprotective mechanism and validated target for the treatment of ischemic stroke. Overexpression of Nln in a mouse model of stroke results in dramatic improvement of stroke outcomes, while pharmacological inhibition aggravates them. Activation of Nln has therefore emerged as an intriguing target for drug discovery efforts for ischemic stroke. Herein, we report the discovery and hit-to-lead optimization of first-in-class Nln activators based on histidine-containing dipeptide hits identified from a virtual screen. Adopting a peptidomimetic approach provided lead compounds that retain the pharmacophoric histidine moiety and possess single-digit micromolar potency over 40-fold greater than the hit scaffolds. These compounds exhibit 5-fold increased brain penetration, significant selectivity over highly homologous peptidases, greater than 65-fold increase in mouse brain stability, and 'drug-like' fraction unbound in the brain.
AB - Peptidase neurolysin (Nln) is an enzyme that functions to cleave various neuropeptides. Upregulation of Nln after stroke has identified the enzyme as a critical endogenous cerebroprotective mechanism and validated target for the treatment of ischemic stroke. Overexpression of Nln in a mouse model of stroke results in dramatic improvement of stroke outcomes, while pharmacological inhibition aggravates them. Activation of Nln has therefore emerged as an intriguing target for drug discovery efforts for ischemic stroke. Herein, we report the discovery and hit-to-lead optimization of first-in-class Nln activators based on histidine-containing dipeptide hits identified from a virtual screen. Adopting a peptidomimetic approach provided lead compounds that retain the pharmacophoric histidine moiety and possess single-digit micromolar potency over 40-fold greater than the hit scaffolds. These compounds exhibit 5-fold increased brain penetration, significant selectivity over highly homologous peptidases, greater than 65-fold increase in mouse brain stability, and 'drug-like' fraction unbound in the brain.
UR - http://www.scopus.com/inward/record.url?scp=85114638950&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85114638950&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00759
DO - 10.1021/acs.jmedchem.1c00759
M3 - Article
C2 - 34436882
AN - SCOPUS:85114638950
SN - 0022-2623
VL - 64
SP - 12705
EP - 12722
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -