Hu Longqin, Taneja Akash, Zahid Husam, Wang Yiling, Yang Min, An Zhihua, Li Xingsheng, Tischfield Jay A, Knight John, Ward Michael D, Sahota Amrik
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.
ACS Med Chem Lett. 2024 Nov 4;15(11):2005-2011. doi: 10.1021/acsmedchemlett.4c00423. eCollection 2024 Nov 14.
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 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 study demonstrating efficacy in preventing urinary CaOx crystal formation in an -knockout mouse model for hyperoxaluria.
高草酸尿症是由草酸尿排泄增加导致草酸钙（CaOx）结石形成引起的。由于缺乏针对高草酸尿症的有效管理策略，我们开展了相关研究，探索作为结石抑制剂的分子模拟物，此前我们曾成功运用这一策略发现了L-胱氨酸结晶的小分子抑制剂，用于预防胱氨酸尿症中的L-胱氨酸结石形成。在此，我们报告发现了一种新型二氧肟酸酯衍生物——草酸二赖氨酸（LH1513），它作为CaOx结晶抑制剂，比柠檬酸盐和丙酮酸盐更有效。通过原子力显微镜（AFM）在微观长度尺度上对晶体生长速率的测量，证实了这种抑制作用。研究发现LH1513的三酯前药具有足够的口服生物利用度，可用于一项初步研究，该研究证明其在高草酸尿症基因敲除小鼠模型中预防尿CaOx晶体形成方面具有疗效。
