Potent Triazolopyridine Myeloperoxidase Inhibitors
| Autor: | Lei Zhao, Scott A. Shaw, Lynn M. Abell, Fred Lo, Gregory A. Locke, Meriah Neissel Valente, Xiaoqin Liu, Paul G. Sleph, Lisa M. Kopcho, Michael Basso, Andrew Quoc Viet, Rangaraj Narayanan, Nicholas R. Wurtz, Franck Duclos, Sutjano Jusuf, Ellen K. Kick, Dilger Andrew K, Ruth R. Wexler, Gayani Fernando, Javed Khan |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Reactive oxygen species biology Organic Chemistry Rational design Active site Inflammation Pharmacology Biochemistry 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry Thioether 030220 oncology & carcinogenesis Myeloperoxidase Drug Discovery biology.protein medicine Triazolopyridine medicine.symptom Peroxidase |
| Popis: | [Image: see text] Myeloperoxidase (MPO) generates reactive oxygen species that potentially contribute to many chronic inflammatory diseases. A recently reported triazolopyrimidine MPO inhibitor was optimized to improve acid stability and remove methyl guanine methyl transferase (MGMT) activity. Multiple synthetic routes were explored that allowed rapid optimization of a key benzyl ether side chain. Crystal structures of inhibitors bound to the MPO active site demonstrated alternate binding modes and guided rational design of MPO inhibitors. Thioether 36 showed significant inhibition of MPO activity in an acute mouse inflammation model after oral dosing. |
| Databáze: | OpenAIRE |
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