Aldosterone Synthase Inhibitor for CKD

醛固酮合酶抑制剂治疗 CKD

基本信息

批准号：
8453692
负责人：
Bert J. W. M. Oehlen
金额：
$ 38.09万
依托单位：
ANGION BIOMEDICA CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-20 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8453692
关键词：
Albuminuria Aldosterone Aldosterone Synthase Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Animal Model Applications Grants Aromatase Benchmarking Blood Pressure CYP11B1 gene CYP11B2 gene CYP19A1 gene CYP3A4 gene Cells Chemistry Chronic Kidney Failure Clinical Management Collagen Creatinine Creatinine clearance measurement Cytochrome P450 Deposition Development Diabetic Nephropathy Disease Dose Drug Exposure Drug Kinetics Enzyme Inhibition Enzymes Fibrosis Functional disorder Future Goals Histopathology Homology Modeling Hydroxyproline Kidney Kidney Diseases Lead Libraries Measurement Mineralocorticoid Receptor Modeling Mus Nephrectomy Obstruction Oral Peptidyl-Dipeptidase A Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Physiological Physiology Play Pre-Clinical Model Production Property Publishing Rattus Renin-Angiotensin-Aldosterone System Rodent Model Role Safety Series Serum Solid Spironolactone System Testing Therapeutic Toxicology Treatment Efficacy Urethral Obstruction Urine Work base clinically relevant clinically significant combat drug efficacy efficacy evaluation efficacy testing inhibitor/antagonist pre-clinical prevent public health relevance research clinical testing small molecule success telmisartan therapeutic effectiveness tool

项目摘要

DESCRIPTION (provided by applicant): The renin-angiotensin-aldosterone system (RAAS) plays a critical role in renal physiology. Inhibitors of angiotensin-converting enzyme (ACE) or angiotensin receptor blockers (ARB) are the mainstay in the clinical management of renal disorders such as chronic kidney disease (CKD). These treatments are thought to work in large part by reducing serum and renal aldosterone levels. However, despite initial success of ACE inhibition or ARB therapy to reduce aldosterone, levels eventually often return to pretreatment levels, thus limiting therapeutic effectiveness of RAAS inhibitors. The clinical significance of th phenomenon of "aldosterone breakthrough" is increasingly recognized. One approach to combat this breakthrough is to inhibit the enzyme responsible for aldosterone production: aldosterone synthase. Despite promising results of tool aldosterone synthase inhibitors in preclinical animal models, no aldosterone synthase inhibitors are currently undergoing clinical evaluation for CKD. From a focused library, Angion has identified a new series of proprietary non- steroidal small molecule inhibitors of aldosterone synthase. The present grant proposal aims to (1) optimize this series of compounds and (2) test efficacy in preclinical models of renal fibrosis.

描述（由申请人提供）：肾素-血管紧张素-醛固酮系统（RAAS）在肾脏生理学中发挥着关键作用。血管紧张素转换酶（ACE）抑制剂或血管紧张素受体阻滞剂（ARB）是慢性肾病（CKD）等肾脏疾病临床治疗的主要药物。人们认为这些治疗在很大程度上是通过降低血清和肾脏醛固酮水平来发挥作用的。然而，尽管 ACE 抑制或 ARB 疗法在降低醛固酮方面取得了初步成功，但其水平最终往往会恢复到治疗前的水平，从而限制了 RAAS 抑制剂的治疗效果。 “醛固酮突破”现象的临床意义日益被人们所认识。应对这一突破的一种方法是抑制负责醛固酮生成的酶：醛固酮合酶。尽管工具醛固酮合酶抑制剂在临床前动物模型中取得了有希望的结果，但目前还没有醛固酮合酶抑制剂正在进行 CKD 的临床评估。 Angion 从一个重点库中鉴定出了一系列新的专有的醛固酮合酶非甾体小分子抑制剂。目前的拨款提案旨在（1）优化该系列化合物以及（2）测试肾纤维化临床前模型的功效。