Design, Synthesis, and Activity Evaluation of Stereoconfigured Tartarate Derivatives as Potential Anti-inflammatory Agents In Vitro and In Vivo
| Autor: | Palwinder Singh, Jashanpreet Kaur, Priya Kumari, Rajbir Bhatti |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences medicine.drug_class Inflammation Algesia Pharmacology 01 natural sciences Anti-inflammatory In vitro 0104 chemical sciences Pathogenesis 010404 medicinal & biomolecular chemistry 03 medical and health sciences Enzyme chemistry In vivo Drug Discovery medicine Molecular Medicine medicine.symptom IC50 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 64:9550-9566 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c00880 |
| Popis: | Preclinical and clinical data reveal that inflammation is strongly correlated with the pathogenesis of a number of diseases including those of cancer, Alzheimer, and diabetes. The inflammatory cascade involves a multitude of cytokines ending ultimately with the activation of COX-2/LOX for the production of prostaglandins and leukotrienes. While the available inhibitors for these enzymes suffer from nonoptimal selectivity, in particular for COX-2, we present here the results of purposely designed tartarate derivatives that exhibit favorable selectivity and significant effectiveness against COX-2 and LOX. Integrated approaches of molecular simulation, organic synthesis, and biochemical/physical experiments identified 15 inhibiting COX-2 and LOX with respective IC50 4 and 7 nM. At a dose of 5 mg kg-1 to Swiss albino mice, 15 reversed algesia by 65% and inflammation by 33% in 2-3 h. We find good agreement between experiments and simulations and use the simulations to rationalize our observations. |
| Databáze: | OpenAIRE |
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