SLC26A3 (DRA) Inhibitors for Treatment of Hyperoxaluria and Nephrolithiasis

摘要 草酸盐是一种阴离子，在人体内没有已知的生物学功能。草酸盐通过饮食摄入， 由肝脏作为代谢废物产生。大部分草酸盐（~90%）由肾脏排泄， 粪便中的一些排泄物。在肾脏中，草酸盐形成难溶性草酸钙晶体，这可能导致 肾结石、肾钙质沉着症和甚至慢性肾病（CKD）。高尿酸是一个主要的危险因素 草酸钙肾结石（占所有结石的2/3），最近 被认为是CKD进展的风险因素。重要的是，某些胃肠道疾病（肥胖症 外科手术、炎症性肠病、胰腺功能不全）与膳食纤维的过度吸收有关。 结肠中的草酸盐、显著的高尿酸和尿结石负荷（即肠高尿酸）。这里我们 提出了一种新的治疗高尿酸的策略，通过阻断结肠中的草酸盐摄取并促进 粪便排泄，预计可减少尿草酸负荷，保护肾脏免受有害的 高尿酸血症的影响。靶是SLC 26 A3，一种阴离子（草酸盐、Cl-、HCO 3-）交换剂，在大肠杆菌中高度表达。 结肠促进草酸摄取。SLC 26 A3抑制是治疗高尿症的一种令人信服的方法， 在具有罕见SLC 26 A3的基因敲除小鼠和人类中，尿草酸排泄减少50- 70 突变。我们最近发现了一流的具有纳摩尔效力的SLC 26 A3抑制剂，并证明了 候选物在高尿酸和草酸盐肾病小鼠模型中的概念验证功效。SLC26a3 抑制剂将作为治疗高尿酸和草酸钙肾结石的一流药物。 认识到拥有后备候选人的重要性，在目标1中进行额外的高通量筛选， 将进行药物化学以鉴定具有纳摩尔效力和良好溶解性的新型支架， 不同的作用位点（细胞内与细胞外）、代谢稳定性和良好的药代动力学。的 目标1中鉴定和优化的化合物将在已建立的高尿酸和草酸盐模型中进行测试 在小鼠肾病中，以及在其他临床相关的高尿症模型中，包括肥胖、囊性 纤维化和减肥手术相关的高尿症，以及原发性高尿症。候选人良好 将在目标3中测试这些模型中的功效的体外和体内毒性。这些建议的目标 本实验的目的是选择一种或两种具有良好动物疗效和优异的SLC 26 A3抑制剂的先导候选物， 进一步临床前开发的安全性特征。

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.