Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1
| Autor: | José A. Gómez-Vidal, Mónica Díaz-Gavilán, Francisco Franco-Montalban, Maria Dolores Moya-Garzon, Eduardo Salido, Manuela Romera, Cristina Martín Higueras, Pablo Peñalver, Miguel X. Fernandes |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment In silico Oxalate Primary hyperoxaluria 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Salicylic acid derivatives Drug Discovery medicine Animals Humans Glyoxylate metabolism Computer Simulation Gene Cells Cultured Transaminases Oxalates Chemistry Immunosuppression medicine.disease Mice Mutant Strains Salicylates Transplantation Mice Inbred C57BL Molecular Docking Simulation Alcohol Oxidoreductases 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Drug Design Hyperoxaluria Primary Hepatocytes Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 61(16) |
| ISSN: | 1520-4804 |
| Popis: | Primary hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease related to glyoxylate metabolism and characterized by accumulation of calcium oxalate crystals. Current therapies involve hepatic and/or renal transplantation, procedures that have significant morbidity and mortality and require long-term immunosuppression. Thus, a pharmacological treatment is urgently needed. We introduce here an unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range, which means a potential use in the treatment of PH1. Though correlation of this phenotypic activity with glycolate oxidase (GO) inhibition is still to be verified, most of the salicylic acids described here are GO inhibitors with IC50 values down to 3 μM. Binding mode of salicylic acids inside GO has been studied using in silico methods, and preliminary structure-activity relationships have been established. The drug-like structure and ease of synthesis of our compounds make them promising hits for structural optimization. |
| Databáze: | OpenAIRE |
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