N-4-aminobenzyl-N'-(2-(2-phenylpyrrolidin)-2-oxoethyl)urea-based inhibitors of cyclophilin D-Preparation of distinct stereoisomers and comparative analysis of their in vitro bioactivity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F25%3A50022510" target="_blank" >RIV/62690094:18470/25:50022510 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11150/25:10509263

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0045206825006236" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0045206825006236</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bioorg.2025.108743" target="_blank" >10.1016/j.bioorg.2025.108743</a>

Jazyk výsledku

angličtina

Název v původním jazyce

N-4-aminobenzyl-N'-(2-(2-phenylpyrrolidin)-2-oxoethyl)urea-based inhibitors of cyclophilin D-Preparation of distinct stereoisomers and comparative analysis of their in vitro bioactivity

Popis výsledku v původním jazyce

Cyclophilin D (CypD) is a mitochondrial enzyme and the key regulator of mitochondrial permeability transition pore (mPTP). Inhibition of CypD/mPTP holds promise as a therapeutic strategy for treatment of variety of diseases including ischemia-reperfusion injury, or neurodegeneration. Compounds based on the N-4-aminobenzyl-N&apos;-(2-(2-phenylpyrrolidin)-2-oxoethyl)urea structural scaffold present the most potent class of smallmolecule CypD inhibitors identified to date. Numerous independent studies on their synthesis and evaluation were published by different research groups. Unfortunately, the results of particular studies cannot be compared due to use of distinct methods of in vitro evaluation and, in most cases, unresolved stereochemistry of prepared chiral compounds. This did not allow for comprehensive analysis to identify the best inhibitors and their structural features. Therefore, we decided to synthesize the most potent inhibitors and their close analogues in form of pure stereoisomers to perform a side-by-side comparison of their inhibition potency and binding affinity to CypD as well as their ability to suppress mPTP opening. In addition, the selectivity of inhibition has been determined using CypA as an off-target. Compound 13(R) was found superior to other tested small molecule inhibitors in all the tested parameters and it was equipotent to the reference inhibitor cyclosporine A.

Název v anglickém jazyce

N-4-aminobenzyl-N'-(2-(2-phenylpyrrolidin)-2-oxoethyl)urea-based inhibitors of cyclophilin D-Preparation of distinct stereoisomers and comparative analysis of their in vitro bioactivity

Popis výsledku anglicky

Cyclophilin D (CypD) is a mitochondrial enzyme and the key regulator of mitochondrial permeability transition pore (mPTP). Inhibition of CypD/mPTP holds promise as a therapeutic strategy for treatment of variety of diseases including ischemia-reperfusion injury, or neurodegeneration. Compounds based on the N-4-aminobenzyl-N&apos;-(2-(2-phenylpyrrolidin)-2-oxoethyl)urea structural scaffold present the most potent class of smallmolecule CypD inhibitors identified to date. Numerous independent studies on their synthesis and evaluation were published by different research groups. Unfortunately, the results of particular studies cannot be compared due to use of distinct methods of in vitro evaluation and, in most cases, unresolved stereochemistry of prepared chiral compounds. This did not allow for comprehensive analysis to identify the best inhibitors and their structural features. Therefore, we decided to synthesize the most potent inhibitors and their close analogues in form of pure stereoisomers to perform a side-by-side comparison of their inhibition potency and binding affinity to CypD as well as their ability to suppress mPTP opening. In addition, the selectivity of inhibition has been determined using CypA as an off-target. Compound 13(R) was found superior to other tested small molecule inhibitors in all the tested parameters and it was equipotent to the reference inhibitor cyclosporine A.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

<a href="/cs/project/NU22J-02-00006" target="_blank" >NU22J-02-00006: Nízkomolekulární inhibitory přechodné mitochondriální propustnosti pro léčbu reperfúzního poškození myokardu</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Bioorganic Chemistry

ISSN

0045-2068

e-ISSN

1090-2120

Svazek periodika

163

Číslo periodika v rámci svazku

August

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

25

Strana od-do

"Article Number: 108743"

Kód UT WoS článku

001533726100001

EID výsledku v databázi Scopus

2-s2.0-105010716298