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Urea transport inhibitors as a new class of diuretics

尿素转运抑制剂作为新型利尿剂

基本信息

批准号：
8816096
负责人：
ALAN S VERKMAN
金额：
$ 34.26万
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：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8816096
关键词：
Acetamides Animal Model Animal Testing Biological Assay Biological Availability Cell Culture Techniques Cell Line Cells Chemicals Clinical Congestive Heart Failure Cytolysis Data Dehydration Development Diuretics Drug Kinetics Edema Endothelium Epithelial Cells Erythrocytes Fluid overload Fluorescence Generations Goals Health Hydration status Inhibitory Concentration 50 Kidney Kinetics Knock-out Knockout Mice Liquid substance MDCK cell Measurement Metabolic Modeling Molecular Monitor Nephrotic Syndrome Oral Osmolalities Outcome Output Pharmaceutical Preparations Pharmacology Physiology Play Property Protein Isoforms Rattus Rectum Renal function Research Rodent Model Role Serum Structure-Activity Relationship Swelling Testing Therapeutic Toxic effect Urea Urine Vasopressins analog assay development base clinically relevant computational chemistry countercurrent chromatography high throughput screening in vivo inhibitor/antagonist knockout gene nitrogen metabolism novel scaffold screening sensor tool transport inhibitor urea transporter urinary water channel

项目摘要

DESCRIPTION (provided by applicant): The generation of a concentrated urine by the kidney involves a countercurrent multiplication mechanism, which is facilitated by urea transporter (UT)-A-type urea transporters in tubule epithelial cells, and a countercurrent exchange mechanism, which is facilitated by UT-B in microvascular (vasa recta) endothelia. Loss of UT function is predicted to disrupt urinary concentrating ability. We propose UTs as novel targets for the development of a new type of diuretic, which we call 'urearetic', with a novel mechanism of action and a unique clinical indication profile. The primary goal of this proposal is to deliver drug-like, validated UT inhibitors for clinical development. Additional deliverables include the generation of potent UT-selective inhibitors as research tools, and, using these tools, to generate new data on renal UT physiology in rodent models by chemical knockout, recognizing its advantages over gene knockout. In Aim 1, a novel high-throughput screen will be used to identify UT inhibitors with different UT isoform selectivity profiles. This aim follows from extensive preliminary data on assay development and identification of UT-B and UT-A1 inhibitors. Screening against each of the major renal UT isoforms, UT-A1, UT-A2 and UT-A3 to identify active compounds for study structure-activity relationships and selectivity profiles will e conducted. In Aim 2, UT inhibition mechanisms and pharmacology of compounds identified in Aim 1 will be determined in order to establish a prioritized list of compounds for animal testing. Target compound properties include high UT inhibition potency (low nM IC50) and good pharmacological profile. Studies will include: (a) using cell culture models - inhibition reversibility, kinetics, sidedness and urea competition; (b) by computational chemistry - the molecular basis of inhibition potency and selectivity; and (c) using rats - pharmacokinetics, renal/urine accumulation and toxicity. In Aim 3, rodent models and UT inhibitors will be used to characterize the role of UTs in urinary concentrating function and to obtain proof-of-concept for UT inhibitor therapy of edema. Target effects of UT inhibitors in vivo include increasing urine output and reducing urinary concentrating ability, and reducing edema in clinically relevant states of fluid accumulation. Studies in rats will include measurements of compound effects on urine output, osmolality and urea concentration, and serum urea concentration, during normal hydration and with dehydration DDAVP. Compound(s) will also be tested in a rat model of edema in congestive heart failure. The outcomes of this proposal will include drug-like, validated UT inhibitors for use as research tools and for clinical development, and new information on the role of UTs in the urinary concentrating mechanism.

描述（由申请人提供）：肾脏产生浓缩尿液涉及逆流增殖机制，这是由小管上皮细胞中的尿素转运蛋白（UT） a型尿素转运蛋白促进的，以及逆流交换机制，这是由微血管（直血管）内皮中的UT- b促进的。UT功能的丧失预计会破坏尿浓缩能力。我们建议ut作为开发一种新型利尿剂的新靶点，我们称之为“urearetic”，具有新的作用机制和独特的临床适应症。本提案的主要目标是交付