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.
The renin-angiotensin-aldosterone system (RAAS) plays a critical role in renal physiology. The direct patho- physiological role of aldosterone in the etiolgy of chronic kidney disease is increasingly recognized. Current inhibitors of the RAAS system are effective in reducing aldosterone, but levels are eventually often found to return to pretreatment levels, thus limiting therapeutic effectiveness such RAAS inhibitors. It is thought that aldosterone breakthrough can be prevented or corrected by directly inhibiting the enzyme aldosterone synthase. Angion has identified a new series of proprietary non-steroidal small molecule inhibitors of aldosterone synthase, which it seeks to further develop into effective therapeutics for chronic kidney disease.