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Discovery of l-Lysine Dioxalate (LH1513) as a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria

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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Med. Chem. Lett. 2024, 15, 11, 2005-2011
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    Letter

    Discovery of l-Lysine Dioxalate (LH1513) as a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria
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    • Longqin Hu*
      Longqin Hu
      Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
      The Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, United States
      *Phone: 848-445-5291. Email: [email protected]
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      Orcidhttps://orcid.org/0000-0002-1799-5652
    • Akash Taneja
      Akash Taneja
      Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
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    • Husam Zahid
      Husam Zahid
      Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
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    • Yiling Wang
      Yiling Wang
      Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
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    • Min Yang
      Min Yang
      Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
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    • Zhihua An
      Zhihua An
      Molecular Design Institute, Department of Chemistry, New York University, New York, New York 10003, United States
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      Orcidhttps://orcid.org/0000-0001-5427-0346
    • Xingsheng Li
      Xingsheng Li
      Department of Urology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
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    • Jay A. Tischfield
      Jay A. Tischfield
      Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
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    • John Knight
      John Knight
      Department of Urology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
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    • Michael D. Ward
      Michael D. Ward
      Molecular Design Institute, Department of Chemistry, New York University, New York, New York 10003, United States
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      Orcidhttps://orcid.org/0000-0002-2090-781X
    • Amrik Sahota
      Amrik Sahota
      Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2024, 15, 11, 2005–2011
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    https://doi.org/10.1021/acsmedchemlett.4c00423
    Published November 4, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    Hyperoxaluria is caused by increased urinary excretion of oxalate leading to the formation of calcium oxalate (CaOx) stones. The lack of effective management strategies for hyperoxaluria prompted us to investigate molecular mimics as stone inhibitors, a strategy that we previously used successfully to discover small molecule inhibitors of l-cystine crystallization for the prevention of l-cystine stone formation in cystinuria. Herein, we report the discovery of l-lysine dioxalate (LH1513), a novel dioxamate derivative, as a more potent inhibitor of CaOx crystallization than citrate and pyruvate. Such inhibition was corroborated by in situ atomic force microscopy (AFM) measurements of crystal growth rates at the microscopic length scale. A triester prodrug of LH1513 was found to have sufficient oral bioavailability for a preliminary in vivo study demonstrating efficacy in preventing urinary CaOx crystal formation in an Agxt-knockout mouse model for hyperoxaluria.

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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2024, 15, 11, 2005–2011
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsmedchemlett.4c00423
    Published November 4, 2024
    Copyright © 2024 American Chemical Society
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