Aldosterone Synthase Inhibitor for CKD

描述（由申请人提供）：肾素-血管紧张素-醛固酮系统（RAAS）在肾脏生理学中起关键作用。血管紧张素转换酶（ACE）抑制剂或血管紧张素受体阻滞剂（ARB）是慢性肾脏疾病（CKD）等肾脏疾病临床治疗的主要药物。这些治疗被认为在很大程度上通过降低血清和肾脏醛固酮水平来起作用。然而，尽管ACE抑制或ARB治疗在降低醛固酮方面取得了初步成功，但最终水平通常会恢复到治疗前水平，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。对抗这一突破的一种方法是抑制负责醛固酮产生的酶：醛固酮合酶。尽管工具醛固酮合成酶抑制剂在临床前动物模型中的结果很有希望，但目前没有醛固酮合成酶抑制剂正在接受CKD的临床评价。从一个集中的图书馆，Angion已经确定了一个新的系列专有的非甾体小分子醛固酮合成酶抑制剂。目前的资助提案旨在（1）优化这一系列化合物和（2）在肾纤维化临床前模型中测试疗效。

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.