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.
Public Health Relevance Statement: Public Health Relevance: 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.
Project Terms: Albuminuria; Aldosterone; Aldosterone Synthase; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Applications Grants; Aromatase; base; Benchmarking; Blood Pressure; Cells; Chemistry; Chronic Kidney Failure; Clinical Management; clinically relevant; clinically significant; Collagen; combat; Creatinine; Creatinine clearance measurement; CYP11B1 gene; CYP11B2 gene; CYP19A1 gene; CYP3A4 gene; Cytochrome P450; Deposition; Development; Diabetic Nephropathy; Disease; Dose; drug efficacy; Drug Exposure; Drug Kinetics; efficacy evaluation; efficacy testing; Enzyme Inhibition; Enzymes; Fibrosis; Functional disorder; Future; Goals; Histopathology; Homology Modeling; Hydroxyproline; inhibitor/antagonist; 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; Pre-Clinical Model; prevent; Production; Property; public health relevance; Publishing; Rattus; Renin-Angiotensin-Aldosterone System; research clinical testing; Rodent Model; Role; Safety; Series; Serum; small molecule; Solid; Spironolactone; success; System; telmisartan; Testing; Therapeutic; therapeutic effectiveness; tool; Toxicology; Treatment Efficacy; Urethral Obstruction; Urine; Work
