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L-Cystine Diamides as Inhibitors of L-Cystine Stone Formation in Cystinuria

L-胱氨酸二酰胺作为胱氨酸尿症中 L-胱氨酸结石形成的抑制剂

基本信息

批准号：
10083210
负责人：
LONGQIN HU
金额：
$ 52.23万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083210
关键词：
Adverse reactions Affect Alkylation Amides Amino Acids Atomic Force Microscopy Binding Biological Assay Biological Availability Bladder Bladder Calculi Cardiotoxicity Cell Membrane Permeability Chronic Collaborations Cost Savings Crystallization Cysteine Cystine Cystinuria Data Development Diamide Diamines Disulfides Dose Drug Interactions Drug Kinetics Effectiveness Ethylenes Evaluation Excretory function Failure Family Fluorescence Future Genetic Diseases Goals Growth Heart Human In Situ In Vitro Kidney Knock-out Knockout Mice Laboratories Lead Life Liver Measures Metabolic Modeling Molecular Morphology Mus Operative Surgical Procedures Oral Organ Patients Pharmaceutical Preparations Pharmacotherapy Piperazines Process Prodrugs Property Recurrence Risk Role Safety Scanning Electron Microscopy Services Site Solubility Sulfhydryl Compounds Surface Testing Time Toxic effect United States National Institutes of Health Urine Visualization Water Wild Type Mouse alkalinity analog aqueous base candidate selection compliance behavior cyclic amine cytotoxicity design disulfide bond drug candidate drug discovery effective therapy efficacy evaluation genotoxicity improved in vitro Assay in vivo inhibitor/antagonist interest male molecular modeling novel strategies pharmacokinetic model pre-clinical preclinical evaluation preclinical study prevent programs rare genetic disorder renal damage

项目摘要

Cystinuria, a genetic disorder of cystine transport, is characterized by excessive excretion of L-cystine in the urine and recurrent cystine stones in the kidneys and, to a lesser extent, in the bladder. Current treatment of cystinuria has not changed over the last three decades. Patients are advised to drink substantial amounts of water (>4 liters/day) to reduce the concentration of free L-cystine in urine and to alkalinize the urine to increase cystine solubility, advice that challenges patient adherence. Drug therapy in severe conditions is limited to two thiol drugs that react with L-cystine to form more soluble mixed disulfides, but these drugs have poor patient compliance due to adverse reactions that, in some cases, may be life-threatening. Thus, there is a need to reduce or eliminate the risks associated with therapy for cystinuria. In this application, we propose a new approach to prevent recurrent cystine stone formation in patients with cystinuria. Our substantive in vitro studies indicate that L-cystine diamides are potent inhibitors of cystine crystallization, which is a required condition for stone formation. Our preliminary in vivo studies indicate that one compound (LH708) from this family is effective in preventing L-cystine stone formation in Slc3a1 knockout mice, which we generated in our laboratories as a model for cystinuria. Building on our in vitro and in vivo data, we will design, synthesize, and evaluate new analogs and prodrugs of L-cystine diamides with sufficient metabolic stability and oral bioavailability that can effectively inhibit L-cystine crystallization in vivo and thus prevent L-cystine stone formation. The effectiveness of these new compounds to inhibit L-cystine crystallization will be tested using a combination of in vitro fluorescence-based solubility and real-time in situ crystal growth inhibition assays. The most effective inhibitors then will be evaluated for their in vivo efficacy, safety, and bioavailability in Slc3a1 knockout mice and for their preclinical ADME-Tox properties. The combined results from these studies will enable the selection of one top drug candidate and one backup candidate for IND-directed preclinical evaluations, for which we will seek assistance from the NIH NCATS program.

胱氨酸尿症是一种胱氨酸转运的遗传性疾病，其特征在于尿液中L-胱氨酸的过量排泄和肾脏中的复发性胱氨酸结石，并且在较小程度上在膀胱中。目前胱氨酸尿症的治疗在过去三十年中没有改变。建议患者饮用大量的水（>4升/天）以降低尿液中游离L-胱氨酸的浓度，并碱化尿液以增加胱氨酸溶解度，这是挑战患者依从性的建议。严重情况下的药物治疗仅限于两种巯基药物，它们与L-胱氨酸反应形成更可溶的混合二硫化物，但由于在某些情况下可能危及生命的不良反应，这些药物的患者依从性较差。因此，需要减少或消除与胱氨酸尿症治疗相关的风险。在本申请中，我们提出了一种新的方法来预防胱氨酸尿症患者复发性胱氨酸结石形成。我们大量的体外研究表明，L-胱氨酸二酰胺是胱氨酸结晶的有效抑制剂，胱氨酸结晶是结石形成的必要条件。我们的初步体内研究表明，来自该家族的一种化合物（LH 708）可有效预防Slc 3a 1敲除小鼠中L-胱氨酸结石形成，该小鼠是我们在实验室中产生的胱氨酸尿症模型。基于我们的体外和体内数据，我们将设计、合成和评估具有足够代谢稳定性和口服生物利用度的L-胱氨酸二酰胺的新类似物和前药，其可以有效地抑制L-胱氨酸在体内结晶，从而防止L-胱氨酸结石形成。这些新化合物抑制L-胱氨酸结晶的有效性将使用体外试验和体外代谢试验的组合进行测试。基于荧光的溶解度和实时原位晶体生长抑制测定。然后将评价最有效的抑制剂在Slc 3a 1敲除小鼠中的体内功效、安全性和生物利用度以及其临床前ADME-Tox性质。这些研究的综合结果将使我们能够选择一种顶级候选药物和一种备用候选药物进行IND指导的临床前评价，为此我们将寻求NIH NCATS计划的帮助。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development of convenient crystallization inhibition assays for structure-activity relationship studies in the discovery of crystallization inhibitors.

开发方便的结晶抑制测定法，用于结晶抑制剂发现中的结构-活性关系研究。

DOI：
10.1007/s00044-023-03061-7
发表时间：
2023
期刊：
Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents
影响因子：
0
作者：
Yang,Jeffrey;Albanyan,Haifa;Wang,Yiling;Yang,Yanhui;Sahota,Amrik;Hu,Longqin
通讯作者：
Hu,Longqin

Design, synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria.

作为胱氨酸尿症的 L-胱氨酸结晶抑制剂的 L-胱氨酸二酰胺的设计、合成和评估。

DOI：
10.1016/j.bmcl.2018.03.024
发表时间：
2018
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
Yang,Yanhui;Albanyan,Haifa;Lee,Sumi;Aloysius,Herve;Liang,Jian-Jie;Kholodovych,Vladyslav;Sahota,Amrik;Hu,Longqin
通讯作者：
Hu,Longqin

Role of Molecular Recognition in l-Cystine Crystal Growth Inhibition.

DOI：
10.1021/acs.cgd.7b00236
发表时间：
2017-05-03
期刊：
Crystal growth & design
影响因子：
3.8
作者：
Poloni LN;Zhu Z;Garcia-Vázquez N;Yu AC;Connors DM;Hu L;Sahota A;Ward MD;Shtukenberg AG
通讯作者：
Shtukenberg AG