Discovery of a novel indole pharmacophore for the irreversible inhibition of myeloperoxidase (MPO) |
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| Institution: | 2. Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States;3. PK Sciences, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States;1. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States;2. Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States;3. PK Sciences, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States;1. School of Pharmacy, Jinan University, Guangzhou 510632, China;2. YZ Health-tech Inc., Hengqin District, Zhuhai 519000, China;3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China;4. Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China;5. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;1. Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1–3, Moscow 119991, Russian Federation;2. EDASA Scientific, Via Stingi 37, San Salvo 66050, Italy;3. Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan;4. Dulbecco Telethon Laboratory of Prions & Amyloids, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, Trento 38123, Italy;5. A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov St. 28, Moscow, Russian Federation;1. Department of Chemistry, Centre for Advanced Studies, Guru Nanak Dev University, Amritsar 143005, India;2. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India;1. Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States;2. Center for Pulmonary Vascular Disease, Duke University Medical Center, Durham, NC 27710, United States;1. School of Chemical Engineering, Beijing Institute of Petrochemical Technology, Beijing 102617, PR China;2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines and Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China;3. Beijing Key Laboratory of Enze Biomass Fine Chemicals, Beijing Institute of Petrochemical Technology, Beijing 102617, PR China |
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| Abstract: | Myeloperoxidase (MPO) activity and subsequent generation of hypochlorous acid has been associated with the killing of host-invading microorganisms (e.g. bacteria, viruses, and fungi). However, during oxidative stress, high MPO activity can damage host tissue and is linked to several chronic inflammatory conditions. Herein, we describe the development of a novel biaryl, indole-pyrazole series of irreversible mechanism-based inhibitors of MPO. Derived from an indole-containing high-throughput screen hit, optimization efforts resulted in potent and selective 6-substituted indoles with good oral bioavailability and in vivo activity. |
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| Keywords: | Peroxidase Myeloperoxidase MPO TPO Indole Irreversible inhibitor Mechanism-based inhibitor |
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