2. Academic Validation
  3. Discovery of l-Lysine Dioxalate (LH1513) as a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria

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

  • ACS Med Chem Lett. 2024 Nov 4;15(11):2005-2011. doi: 10.1021/acsmedchemlett.4c00423.
Longqin Hu 1 2,  Akash Taneja 1,  Husam Zahid 1,  Yiling Wang 1,  Min Yang 3,  Zhihua An 4,  Xingsheng Li 5,  Jay A Tischfield 3,  John Knight 5,  Michael D Ward 4,  Amrik Sahota 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.
  • 2 The Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, United States.
  • 3 Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.
  • 4 Molecular Design Institute, Department of Chemistry, New York University, New York, New York 10003, United States.
  • 5 Department of Urology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.
PMID: 39563801 DOI: 10.1021/acsmedchemlett.4c00423
Abstract

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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