Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable,selective, and reversible inhibitors of myeloperoxidase |
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| Affiliation: | 1. Synthia LLC, Davis, CA 95616, United States;2. Department of Entomology and Nematology, One Shields Ave, University of California-Davis, Davis, CA 95616, United States;3. EicOsis Human Health, 140 B Street, Suite 5, Number 346, Davis, CA 95616, United States;1. College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea;2. Infectious Disease Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea;3. Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea;1. State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China;2. Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China;3. Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, 725 South Wan Ping Road, Shanghai, 200032, China;1. Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, United Kingdom;2. Laboratory of Drug Design and Discovery, Department of Chemistry, China Pharmaceutical University, Nanjing 211198, China;1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK;2. Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, UK;3. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK |
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| Abstract: | 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. |
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| Keywords: | Myeloperoxidase Atherosclerosis Triazolopyridine ADP" },{" #name" :" keyword" ," $" :{" id" :" k0025" }," $$" :[{" #name" :" text" ," _" :" adenosine diphosphate APF" },{" #name" :" keyword" ," $" :{" id" :" k0035" }," $$" :[{" #name" :" text" ," _" :" aminophenyl fluorescein AR" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" amplex red total exposure Cl-Tyr" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" chlorotyrosine maximum plasma concentration CYP" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" cytochrome P450 dba" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," _" :" dibenzylideneacetone DCM" },{" #name" :" keyword" ," $" :{" id" :" k0105" }," $$" :[{" #name" :" text" ," _" :" dichloromethane HDL" },{" #name" :" keyword" ," $" :{" id" :" k0115" }," $$" :[{" #name" :" text" ," _" :" high density lipoprotein I.V." },{" #name" :" keyword" ," $" :{" id" :" k0125" }," $$" :[{" #name" :" text" ," _" :" intravenous LDL" },{" #name" :" keyword" ," $" :{" id" :" k0135" }," $$" :[{" #name" :" text" ," _" :" low density lipoprotein MGMT" },{" #name" :" keyword" ," $" :{" id" :" k0145" }," $$" :[{" #name" :" text" ," _" :" methyl guanine methyl transferase MPO" },{" #name" :" keyword" ," $" :{" id" :" k0155" }," $$" :[{" #name" :" text" ," _" :" myeloperoxidase PAMPA" },{" #name" :" keyword" ," $" :{" id" :" k0165" }," $$" :[{" #name" :" text" ," _" :" parallel artificial membrane permeability assay ROS" },{" #name" :" keyword" ," $" :{" id" :" k0175" }," $$" :[{" #name" :" text" ," _" :" reactive oxygen species TEA" },{" #name" :" keyword" ," $" :{" id" :" k0185" }," $$" :[{" #name" :" text" ," _" :" triethylamine TES" },{" #name" :" keyword" ," $" :{" id" :" k0195" }," $$" :[{" #name" :" text" ," _" :" triethylsilyl TFA" },{" #name" :" keyword" ," $" :{" id" :" k0205" }," $$" :[{" #name" :" text" ," _" :" trifluoroacetic acid THF" },{" #name" :" keyword" ," $" :{" id" :" k0215" }," $$" :[{" #name" :" text" ," _" :" tetrahydrofuran TPO" },{" #name" :" keyword" ," $" :{" id" :" k0225" }," $$" :[{" #name" :" text" ," _" :" thyroid peroxidase TrCl" },{" #name" :" keyword" ," $" :{" id" :" k0235" }," $$" :[{" #name" :" text" ," _" :" trityl chloride |
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