SLC26A3 (DRA) Inhibitors for Treatment of Hyperoxaluria and Nephrolithiasis

用于治疗高草酸尿症和肾结石的 SLC26A3 (DRA) 抑制剂

基本信息

批准号：
10055485
负责人：
Onur Cil
金额：
$ 32.3万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-22 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10055485
关键词：
ABCB1 gene Acute Animal Model Anions Back Bicarbonates Binding Proteins Biological Availability Biological Process Calcium Calcium Oxalate Cells Chemicals Chemistry Chlorides Chronic Kidney Failure Clinical Colon Crystallization Cystic Fibrosis Data Deposition Development Diet Disease Progression Dose Drug Kinetics Enteral Enzymes Excretory function Exocrine pancreatic insufficiency Feces Food Frequencies G-Protein-Coupled Receptors Gastric Bypass Gastrointestinal Diseases General Population Goals Histology Human Hyperoxaluria In Vitro Industry Standard Inflammatory Bowel Diseases Ingestion Intestines Ion Channel Kidney Kidney Calculi Kidney Diseases Knock-in Knockout Mice Lead Liver Metabolic Modeling Mus Mutation Nephrocalcinosis Nephrolithiasis Obese Mice Obesity Oral Oxalates Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Plasma Proteins Primary Hyperoxaluria Property Rattus Research Contracts Risk Risk Factors Rodent Model Route SLC26A3 gene Safety Serum Site Sodium Solubility Surface Testing Therapeutic Tissues Toxic effect Toxicity Tests Urinary Calculi Urine Waste Products absorption animal efficacy bariatric surgery clinically relevant compound 30 drug candidate efficacy study efficacy testing experimental study extracellular high throughput screening in vitro testing in vivo inhibitor/antagonist lead candidate mouse model nanomolar novel novel strategies preclinical development programs renal calcium scaffold screening small molecule treatment strategy uptake urinary

项目摘要

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.

抽象的草酸盐是一个阴离子，在人类中没有已知的生物学功能。草酸盐通过饮食摄入，也是由肝脏作为代谢废物产生。大多数草酸盐（〜90％）被肾脏排泄粪便中的一些排泄物。在肾脏中，草酸盐形成不可溶的草酸钙晶体，可以导致肾结石病，肾上腺热病甚至慢性肾脏病（CKD）。 Hyperoxaluria是主要危险因素用于草酸钙肾结石（所有石头的最常见类型2/3），最近被公认为是CKD进展的危险因素。重要的是，某些胃肠道疾病（减肥手术，炎症性肠病，胰腺功能不全）与饮食的超吸收有关在结肠中草酸盐，明显的高黄油和尿石负担（即肠催眠尿症）。在这里，我们提出了一种通过阻塞结肠中的草酸盐吸收并促进的新型效果的新型策略粪便排泄，预计将减轻草酸盐负担并保护肾脏免受不利影响高黄油的作用。该靶标是Slc26a3，一个高度表达的阴离子（草酸盐，Cl-，Hco3-）交换器结肠促进草酸盐吸收。 SLC26A3抑制是一种令人信服的方法，用于治疗高黄油在敲除小鼠和稀有SLC26A3的淘汰小鼠和人类中，尿液草酸盐排泄量降低50-70％。突变。我们最近发现了具有纳摩尔效力的第一类SLC26A3抑制剂，并证明了候选者在高黄油和草酸盐肾病的小鼠模型中的概念验证疗效。 SLC26A3 抑制剂将作为高黄油和草酸钙肾结石的第一类药物。认识到有备份候选人的重要性，在AIM 1额外的高通量筛查和将进行药物化学以识别具有纳摩尔效力和良好溶解度的新型支架不同的作用部位（细胞内与细胞外），代谢稳定性和良好的药代动力学。这在AIM 1中鉴定和优化的化合物将在已建立的高黄油和草酸盐模型中进行测试小鼠的肾病以及其他临床上相关的高氧化尿症，包括肥胖，囊性纤维化和减肥手术相关的高黄油和原发性高黄油。候选人很好这些模型中的功效将在AIM 3中测试，以实现体外和体内毒性。这些提议的目标实验是选择具有良好动物疗效和出色的一个铅候选slc26a3抑制剂安全性概况，用于进一步的临床前开发。