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
The result's identifiers
Result code in 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>
Alternative codes found
RIV/00216208:11150/25:10509263
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
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
Original language description
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'-(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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30107 - Medicinal chemistry
Result continuities
Project
<a href="/en/project/NU22J-02-00006" target="_blank" >NU22J-02-00006: Small-molecule inhibitors of mitochondrial permeability transition for treatment of myocardial ischemia-reperfusion injury</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Bioorganic Chemistry
ISSN
0045-2068
e-ISSN
1090-2120
Volume of the periodical
163
Issue of the periodical within the volume
August
Country of publishing house
US - UNITED STATES
Number of pages
25
Pages from-to
"Article Number: 108743"
UT code for WoS article
001533726100001
EID of the result in the Scopus database
2-s2.0-105010716298