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Discovery of A20 with 4-(2-methoxyphenyl)-1H-pyrazole scaffold as a potent and selective ROCK2 inhibitor.

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Názov: Discovery of A20 with 4-(2-methoxyphenyl)-1H-pyrazole scaffold as a potent and selective ROCK2 inhibitor.
Autori: Wang J; Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China., Peng B; Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China., Liang G; Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China., Zhao Y; Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China. Electronic address: zhaoyan@immu.edu.cn., Gao X; Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China., Zhao Y; Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China., Ga L; Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China., Li R; Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China. Electronic address: 20150172@immu.edu.cn., Ma Y; Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China. Electronic address: 20120311@immu.edu.cn.
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2025 Dec 15; Vol. 129, pp. 130391. Date of Electronic Publication: 2025 Aug 29.
Spôsob vydávania: Journal Article
Jazyk: English
Informácie o časopise: Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE
Imprint Name(s): Publication: Oxford : Elsevier Science Ltd
Original Publication: Oxford ; New York : Pergamon Press, c1991-
Výrazy zo slovníka MeSH: rho-Associated Kinases*/antagonists & inhibitors , rho-Associated Kinases*/metabolism , Pyrazoles*/chemistry , Pyrazoles*/pharmacology , Pyrazoles*/chemical synthesis , Protein Kinase Inhibitors*/chemistry , Protein Kinase Inhibitors*/pharmacology , Protein Kinase Inhibitors*/chemical synthesis , Drug Discovery*, Structure-Activity Relationship ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Dose-Response Relationship, Drug
Abstrakt: Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Rho-associated protein kinase 2 (ROCK2) has become a promising therapeutic target for diseases such as neurological disorders and fibrosis. In this study, structural optimization based on the binding mode of lead compound M214 and ROCK2 was conducted and compound A20 with a 4-(2-methoxyphenyl)-1H-pyrazole scaffold exhibited superior inhibitory activity against ROCK2 with IC 50 value of 0.18 μM and inhibited ROCK1 with IC 50 value of 3.0 μM. Molecular docking study showed that hydrogen bond interactions between pyrazole ring of A20 and Met172 and Glu170 of ROCK2 played key roles in enhancing inhibitory activity.
(Copyright © 2025. Published by Elsevier Ltd.)
Contributed Indexing: Keywords: Molecular docking; ROCK2 inhibitor; Structure-activity relationship; Synthesis
Substance Nomenclature: EC 2.7.11.1 (rho-Associated Kinases)
0 (Pyrazoles)
EC 2.7.11.1 (ROCK2 protein, human)
0 (Protein Kinase Inhibitors)
Entry Date(s): Date Created: 20250831 Date Completed: 20250922 Latest Revision: 20250922
Update Code: 20250923
DOI: 10.1016/j.bmcl.2025.130391
PMID: 40886899
Databáza: MEDLINE
Popis
Abstrakt:Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br />Rho-associated protein kinase 2 (ROCK2) has become a promising therapeutic target for diseases such as neurological disorders and fibrosis. In this study, structural optimization based on the binding mode of lead compound M214 and ROCK2 was conducted and compound A20 with a 4-(2-methoxyphenyl)-1H-pyrazole scaffold exhibited superior inhibitory activity against ROCK2 with IC <subscript>50</subscript> value of 0.18 μM and inhibited ROCK1 with IC <subscript>50</subscript> value of 3.0 μM. Molecular docking study showed that hydrogen bond interactions between pyrazole ring of A20 and Met172 and Glu170 of ROCK2 played key roles in enhancing inhibitory activity.<br /> (Copyright © 2025. Published by Elsevier Ltd.)
ISSN:1464-3405
DOI:10.1016/j.bmcl.2025.130391