Discovery\nof l‑Lysine Dioxalate (LH1513)\nas a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria

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