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Potent Triazolopyridine Myeloperoxidase Inhibitors

  • Nicholas R. Wurtz*
    Nicholas R. Wurtz
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
    *Phone: 609-466-5099. E-mail: [email protected]
  • Andrew Viet
    Andrew Viet
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
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  • Scott A. Shaw
    Scott A. Shaw
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
  • Andrew Dilger
    Andrew Dilger
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
  • Meriah N. Valente
    Meriah N. Valente
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
  • Javed A. Khan
    Javed A. Khan
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
  • Sutjano Jusuf
    Sutjano Jusuf
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
  • Rangaraj Narayanan
    Rangaraj Narayanan
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
  • Gayani Fernando
    Gayani Fernando
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
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    Fred Lo
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
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    Xiaoqin Liu
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
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  • Gregory A. Locke
    Gregory A. Locke
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
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    Lisa Kopcho
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
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  • Lynn M. Abell
    Lynn M. Abell
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
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    Paul Sleph
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
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    Michael Basso
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
  • Lei Zhao
    Lei Zhao
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
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  • Ruth R. Wexler
    Ruth R. Wexler
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
  • Franck Duclos
    Franck Duclos
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
  • , and 
  • Ellen K. Kick
    Ellen K. Kick
    Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States
Cite this: ACS Med. Chem. Lett. 2018, 9, 12, 1175–1180
Publication Date (Web):November 1, 2018
https://doi.org/10.1021/acsmedchemlett.8b00308
Copyright © 2018 American Chemical Society

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    Abstract

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    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.

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    This article is cited by 16 publications.

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    8. S. C. Butani, M. K. Vekariya, P. V. Dholaria, K. M. Kapadiya, N. D. Desai. Copper(I)-Catalyzed Click Chemistry-Based Synthesis and Antimicrobial Evaluation of Triazolopyridine–Triazole Congeners. Russian Journal of Organic Chemistry 2022, 58 (3) , 405-411. https://doi.org/10.1134/S1070428022030204
    9. Ayşe Ünlü, Kerem Teralı, Zübeyde Uğurlu Aydın, Ali A. Dönmez, Hasan Soliman Yusufoğlu, İhsan Çalış. Isolation, Characterization and In Silico Studies of Secondary Metabolites from the Whole Plant of Polygala inexpectata Peşmen & Erik. Molecules 2022, 27 (3) , 684. https://doi.org/10.3390/molecules27030684
    10. Lucyna Dymińska, Jerzy Hanuza, Jan Janczak, Maciej Ptak, Radosław Lisiecki. The Structural and Optical Properties of 1,2,4-Triazolo[4,3-a]pyridine-3-amine. Molecules 2022, 27 (3) , 721. https://doi.org/10.3390/molecules27030721
    11. Héctor Barbero, Carlos Díez-Poza, Laura Fernández-Peña, Asunción Barbero. Bicyclic 5-6 Systems: Four Heteroatoms 3:1. 2022, 395-418. https://doi.org/10.1016/B978-0-12-409547-2.14894-2
    12. Carol H. Hu, Meriah W. Neissel Valente, O. Scott Halpern, Sutjano Jusuf, Javed A. Khan, Gregory A. Locke, Gerald J. Duke, Xiaoqin Liu, Franck J. Duclos, Ruth R. Wexler, Ellen K. Kick, Joanne M. Smallheer. Small molecule and macrocyclic pyrazole derived inhibitors of myeloperoxidase (MPO). Bioorganic & Medicinal Chemistry Letters 2021, 42 , 128010. https://doi.org/10.1016/j.bmcl.2021.128010
    13. Michael J. Davies. Myeloperoxidase: Mechanisms, reactions and inhibition as a therapeutic strategy in inflammatory diseases. Pharmacology & Therapeutics 2021, 218 , 107685. https://doi.org/10.1016/j.pharmthera.2020.107685
    14. Jalal Soubhye, Pierre Van Antwerpen, François Dufrasne. A patent review of myeloperoxidase inhibitors for treating chronic inflammatory syndromes (focus on cardiovascular diseases, 2013-2019). Expert Opinion on Therapeutic Patents 2020, 30 (8) , 595-608. https://doi.org/10.1080/13543776.2020.1780210
    15. E. G. Paronikyan, Sh. Sh. Dashyan, S. S. Mamyan. Synthesis and Thione–Thiol Tautomerism of 5-Thioxopyrano[3,4-c][1,2,4]triazolo[4,3-a]pyridines. Russian Journal of Organic Chemistry 2020, 56 (8) , 1359-1366. https://doi.org/10.1134/S1070428020080059
    16. Anup Patnaik, Laura Axford, Lin Deng, Evan Cohick, Xianglin Ren, Sally Loi, Sam Kecman, Micah Hollis-Symynkywicz, Tyler J. Harrison, Julien P.N. Papillon, Natalie Dales, Lawrence G. Hamann, Lac Lee, Jean B. Regard, Jovita Marcinkeviciene, Martin L. Marro, Andrew W. Patterson. Discovery of a novel indole pharmacophore for the irreversible inhibition of myeloperoxidase (MPO). Bioorganic & Medicinal Chemistry 2020, 28 (12) , 115548. https://doi.org/10.1016/j.bmc.2020.115548

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