Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase
| Autor: | Arathi Krishnakumar, Lisa M. Kopcho, Michael Basso, Benjamin P. Vokits, Glenn H. Cantor, Sutjano Jusuf, Lei Zhao, Lynn M. Abell, Ashok Dongre, Javed Khan, Steven A. Spronk, Gregory A. Locke, Gerald J. Duke, Andrew Quoc Viet, Scott A. Shaw, Franck Duclos, Ellen K. Kick, Joelle M. Onorato, Charles G. Clark, Ruth R. Wexler, Dilger Andrew K, Ji Gao |
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| Rok vydání: | 2020 |
| Předmět: |
Hypochlorous acid
Pyridines Clinical Biochemistry Pharmaceutical Science Endogeny 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Thyroid peroxidase In vivo DNA Repair Protein Drug Discovery Humans Enzyme Inhibitors Molecular Biology Peroxidase biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Triazoles Antimicrobial 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry chemistry Myeloperoxidase biology.protein Molecular Medicine Triazolopyridine |
| Zdroj: | Bioorganicmedicinal chemistry. 28(22) |
| ISSN: | 1464-3391 |
| Popis: | Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT). Structure-based drug design was employed to discover benzyl triazolopyridines with improved MPO potency, as well as acid stability, no reactivity with MGMT, and selectivity against thyroid peroxidase (TPO). Structure-activity relationships, a crystal structure of the MPO-inhibitor complex, and acute in vivo pharmacodynamic data are described herein. |
| Databáze: | OpenAIRE |
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