Synthesis and evaluation of a novel class of spiro[chromene-2,2'-indoline] derivatives as potent inhibitors of peptidylarginine deiminase IV to treat rheumatoid arthritis.
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| Názov: | Synthesis and evaluation of a novel class of spiro[chromene-2,2'-indoline] derivatives as potent inhibitors of peptidylarginine deiminase IV to treat rheumatoid arthritis. |
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| Autori: | Yang CW; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, ROC., Lee YZ; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, ROC., Hsu HY; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, ROC., Lee SJ; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, ROC. Electronic address: slee@nhri.org.tw. |
| Zdroj: | European journal of medicinal chemistry [Eur J Med Chem] 2025 Nov 15; Vol. 298, pp. 117985. Date of Electronic Publication: 2025 Jul 19. |
| Spôsob vydávania: | Journal Article |
| Jazyk: | English |
| Informácie o časopise: | Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Paris : Editions Scientifiques Elsevier Original Publication: Paris, S.E.C.T. [etc.] |
| Výrazy zo slovníka MeSH: | Arthritis, Rheumatoid*/drug therapy , Arthritis, Rheumatoid*/metabolism , Protein-Arginine Deiminase Type 4*/antagonists & inhibitors , Protein-Arginine Deiminase Type 4*/metabolism , Enzyme Inhibitors*/chemical synthesis , Enzyme Inhibitors*/pharmacology , Enzyme Inhibitors*/chemistry , Enzyme Inhibitors*/therapeutic use , Indoles*/chemistry , Indoles*/chemical synthesis , Indoles*/pharmacology , Indoles*/therapeutic use , Spiro Compounds*/chemical synthesis , Spiro Compounds*/chemistry , Spiro Compounds*/pharmacology , Benzopyrans*/chemistry , Benzopyrans*/chemical synthesis , Benzopyrans*/pharmacology , Protein-Arginine Deiminases*/antagonists & inhibitors , Protein-Arginine Deiminases*/metabolism, Animals ; Mice ; Structure-Activity Relationship ; Molecular Structure ; Humans ; Dose-Response Relationship, Drug ; Male ; Arthritis, Experimental/drug therapy ; Arthritis, Experimental/chemically induced |
| Abstrakt: | Competing Interests: Declaration of competing interest The authors declare no conflict of interest. Peptidylarginine deiminase isoform 4 (PADI4) is a potential therapeutic target for treatment of rheumatoid arthritis. Auto-antibodies induced by the dysregulated catalysis of peptidylarginine into peptidylcitrulline by PADI4 can cause the onset and progression of rheumatoid arthritis. Herein, we report a novel class of spiro[chromene-2,2'-indoline] derivatives which were synthesized and optimized from a hit discovered by screening two libraries with 3760-members of natural products and derivatives for PADI4 inhibitors. In vitro, our derivatives were proved capable of potently inhibiting PADI4 and diminishing cellular citrullination; in vivo, the representative compound 7, 6,8-dimethoxy-1',3',3'-trimethylspiro[chromene-2,2'-indoline], effectively ameliorated the severity and pathologic progress of collagen type II antibody/LPS induced rheumatoid arthritis in a mouse model. This work establishes compound 7 and the related potent compounds worthy of further study and development to treat rheumatoid arthritis, and validates PADI4 as a therapeutic target for this purpose. (Copyright © 2025 Elsevier Masson SAS. All rights reserved.) |
| Contributed Indexing: | Keywords: Arginine; Citrullination; Citrulline; Inflammation; Peptidylarginine deiminase; Rheumatoid arthritis |
| Substance Nomenclature: | EC 3.5.3.15 (Protein-Arginine Deiminase Type 4) 0 (Enzyme Inhibitors) 0 (Indoles) 0 (Spiro Compounds) 0 (Benzopyrans) EC 3.5.3.15 (Protein-Arginine Deiminases) EC 3.5.3.15 (PADI4 protein, human) 6DPT9AB2NK (indoline) |
| Entry Date(s): | Date Created: 20250727 Date Completed: 20250826 Latest Revision: 20250904 |
| Update Code: | 20250905 |
| DOI: | 10.1016/j.ejmech.2025.117985 |
| PMID: | 40714618 |
| Databáza: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Competing Interests: Declaration of competing interest The authors declare no conflict of interest.<br />Peptidylarginine deiminase isoform 4 (PADI4) is a potential therapeutic target for treatment of rheumatoid arthritis. Auto-antibodies induced by the dysregulated catalysis of peptidylarginine into peptidylcitrulline by PADI4 can cause the onset and progression of rheumatoid arthritis. Herein, we report a novel class of spiro[chromene-2,2'-indoline] derivatives which were synthesized and optimized from a hit discovered by screening two libraries with 3760-members of natural products and derivatives for PADI4 inhibitors. In vitro, our derivatives were proved capable of potently inhibiting PADI4 and diminishing cellular citrullination; in vivo, the representative compound 7, 6,8-dimethoxy-1',3',3'-trimethylspiro[chromene-2,2'-indoline], effectively ameliorated the severity and pathologic progress of collagen type II antibody/LPS induced rheumatoid arthritis in a mouse model. This work establishes compound 7 and the related potent compounds worthy of further study and development to treat rheumatoid arthritis, and validates PADI4 as a therapeutic target for this purpose.<br /> (Copyright © 2025 Elsevier Masson SAS. All rights reserved.) |
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| ISSN: | 1768-3254 |
| DOI: | 10.1016/j.ejmech.2025.117985 |