Structure-Activity Studies of Novel Di-substituted [1,2,5]oxadiazolo [3,4-b]pyrazine Analogs Targeting the A-loop Regulatory Site of p38 MAP Kinase
| Autor: | Pedro Marset Campos, Juan J. Perez, Miguel de Vega, Patricia Gomez-Gutierrez, Esther Carrasco, Angel Messeguer |
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| Přispěvatelé: | Universitat Politècnica de Catalunya. Departament d'Enginyeria Química, Universitat Politècnica de Catalunya. GBMI - Grup de Biotecnologia Molecular i Industrial |
| Rok vydání: | 2022 |
| Předmět: |
AAA Domain
Pyrazine Stereochemistry p38 mitogen-activated protein kinases Química farmacèutica Regulatory site MAPK inhibitors 4-b]pyrazine derivatives Non-competitive kinase inhibitors p38 Mitogen-Activated Protein Kinases 1 2 5-oxadiazole derivatives Biochemistry furazano[3 4-b]pyrazine derivatives chemistry.chemical_compound Enginyeria química [Àrees temàtiques de la UPC] 5-oxadiazole derivatives Furazano[3 Drug Discovery Humans Pharmacology Molecular Structure biology Orthosteric ligands Macrophages Organic Chemistry kinome Loop (topology) IL-1β inhibitors chemistry Pyrazines Mitogen-activated protein kinase biology.protein Molecular Medicine IL-1ß inhibitors Pharmaceutical chemistry |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 0929-8673 |
| DOI: | 10.2174/0929867328666210712165659 |
| Popis: | In the quest for novel allosteric inhibitors of the p38 MAP kinase, we recently described the A-loop regulatory site, identified through molecular modeling studies together with the disclosure of a small molecule hit with a moderate inhibitory profile. Starting from this structure, we subsequently identified two additional hits with simpler molecular structures from an in silico screening study, using a substructure search in the SciFinder database. After corroboration of their inhibitory profile, analysis of their structures permitted to conclude about the suitability of the [1,2,5]oxadiazolo[3,4-b]pyrazine (furazano[3,4-b]pyrazine) scaffold for the development of potent A-loop regulatory site p38 MAP kinase inhibitors. Accordingly, we report the synthesis and pharmacological evaluation of a series of di-substituted analogs with a potent inhibitory profile of p38 MAP kinase, as shown by in vitro assays of their capability to inhibit IL-1β secretion in human monocyte-derived macrophages. |
| Databáze: | OpenAIRE |
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