SLC26A3 (DRA) Inhibitors for Treatment of Hyperoxaluria and Nephrolithiasis

摘要 草酸是一种阴离子，在人体内没有已知的生物功能。草酸是通过饮食摄入的，而且 由肝脏作为代谢废物产生。大部分草酸(~90%)是由肾脏排泄的 大便中有一些排泄物。在肾脏中，草酸形成难于溶解的草酸钙晶体，这可能导致 肾结石、肾钙素沉着症，甚至慢性肾脏病(CKD)。高草酸尿是一个主要的危险因素。 草酸钙肾结石(最常见的类型，占所有结石的三分之二)，最近 被认为是慢性肾脏病进展的危险因素。重要的是，某些胃肠道疾病(肥胖 手术、炎症性肠病、胰腺功能不全)与饮食的高吸收有关 结肠草酸、明显高草酸尿和尿结石负荷(即肠源性高草酸尿)。在这里，我们 提出一种通过阻断结肠草酸摄取和促进草酸代谢来治疗高草酸尿症的新策略 大便排泄，据预测，这将减少尿草酸负荷，保护肾脏免受有害物质的伤害 高草酸尿症的影响。目标是SLC26A3，一种阴离子(草酸、氯、HCO3-)交换剂，在 结肠促进草酸的摄取。SLC26A3抑制是治疗高草酸尿AS的一种引人注目的方法 提示罕见SLC26A3基因敲除小鼠和人类尿草酸排泄量降低50%-70% 突变。我们最近发现了一流的具有纳摩尔效力的SLC26A3抑制剂，并证明了 在高草酸尿和草酸肾病小鼠模型中的候选概念验证有效性。SLC26A3 抑制剂将被推进为治疗高草酸尿和草酸钙肾结石的一线药物。 认识到拥有后备候选人的重要性，在目标1中增加了高通量筛查和 将进行药物化学以确定具有纳摩尔效力和良好的溶解性的新型支架 作用部位明确(细胞内和细胞外)、代谢稳定性和良好的药代动力学。这个 在目标1中确定和优化的化合物将在已建立的高草酸尿症和草酸盐模型中进行测试 小鼠的肾病，以及其他临床相关的高草酸尿症模型，包括肥胖、囊性 纤维化和减肥手术相关的高草酸尿，以及原发性高草酸尿。优秀的应聘者 这些模型的疗效将在AIM 3中进行体外和体内毒性测试。这些建议的目标是 实验是筛选出一到两个动物效果好、性能优异的候选先导SLC26A3抑制剂 进一步临床前开发的安全性简介。

ABSTRACT Oxalate is an anion with no known biological function in humans. Oxalate is ingested through diet and also generated by liver as a metabolic waste product. The majority of oxalate (~90%) is excreted by the kidney with some excretion in stool. In the kidney, oxalate forms poorly soluble calcium oxalate crystals which can lead to nephrolithiasis, nephrocalcinosis and even chronic kidney disease (CKD). Hyperoxaluria is a major risk factor for calcium oxalate kidney stones (the most common type constituting 2/3 of all stones), and recently recognized as a risk factor for CKD progression. Importantly, certain gastrointestinal diseases (bariatric surgery, inflammatory bowel disease, pancreatic insufficiency) are associated with hyperabsorption of dietary oxalate in colon, significant hyperoxaluria and urinary stone burden (i.e. enteric hyperoxaluria). Here, we propose a novel strategy for treatment of hyperoxaluria by blocking oxalate uptake in colon and promoting stool excretion, which is predicted to reduce urinary oxalate burden and protect kidneys from the detrimental effects of hyperoxaluria. The target is SLC26A3, an anion (oxalate, Cl-, HCO3-) exchanger highly expressed in colon facilitating oxalate uptake. SLC26A3 inhibition is a compelling approach for treatment of hyperoxaluria as suggested by 50-70% lower urine oxalate excretion in knock-out mice and humans with rare SLC26A3 mutations. We recently discovered first-in-class SLC26A3 inhibitors with nanomolar potency and demonstrated proof-of-concept efficacy of a candidate in mouse models of hyperoxaluria and oxalate nephropathy. SLC26A3 inhibitors will be advanced as first-in-class drugs for hyperoxaluria and calcium oxalate kidney stones. Recognizing the importance of having back-up candidates, in Aim 1 additional high-throughput screening and medicinal chemistry will be done to identify novel scaffolds with nanomolar potency and good solubility with distinct sites of action (intracellular vs. extracellular), metabolic stability and good pharmacokinetics. The compounds identified and optimized in Aim 1 will be tested in established models of hyperoxaluria and oxalate nephropathy in mice, as well as in other clinically relevant models of hyperoxaluria including obesity, cystic fibrosis and bariatric surgery-associated hyperoxaluria, and primary hyperoxaluria. Candidates with good efficacy in these models will be tested in Aim 3 for in vitro and in vivo toxicity. The goal of these proposed experiments is to select one or two lead candidate SLC26A3 inhibitors with good animal efficacy and excellent safety profile for further pre-clinical development.