TRPC6 Antagonists as Therapeutics for Chronic Kidney Disease

DESCRIPTION provided by applicant According to the United States Renal Data System focal and segmental glomerulosclerosis FSGS is the most common histopathological finding in primary nephrotic syndrome patients with end stage renal disease ESRD Treatment options in primary forms of FSGS are limited poorly tolerated and fail to produce a sustained remission in as many as half of these patients Moreover primary FSGS often recurs after kidney transplantation leading inexorably to graft failure in as many as of cases As such there is a large unmet need for novel pharmacotherapies to slow or prevent progression of renal failure in these diseases TRPC channels are expressed at abnormally high levels in podocytes in primary FSGS and modulation of their function has been shown to affect the slit diaphragm Exposure to serum from patients with FSGS results in hyperactivation of podocyte TRPC channels in response to mechanical stimuli and a similar pattern is observed in a rat model of secondary FSGS Moreover research in mouse models has shown that knock outs that eliminate glomerular TRPC expression reduce albuminuria evoked by chronic angiotensin or albumin overload This and other data suggest that inhibition of TRPC channels represents a therapeutic strategy for this class of glomerular diseases Algomedix has discovered and characterized a novel series of potent TRP antagonists with drug like properties which block human TRPC channels A unique feature of these novel compounds is that they block activation of rodent TRPC channels by Angiotensin II OAG or mechanical activation with similar nanomolar IC s This research will expand on the initial active compounds in this series to develop a series of novel first in class antagonists characterize their potency and selectivity in cell lines test their ability to block human mutated TRPC channels known to cause familial FSGS and examine their ability to inhibit endogenously expressed TRPC channels in podocytes A key feature of these studies in an ex vivo model of podocytes will be to analyze antagonist activity using multiple modes of activation including mechanical which may be the most relevant for translation to clinical efficacy in FSGS These studies will yield a lead and backup compounds ready for advancement to in vivo studies In Phase studies the efficacy of the lead and backup compounds will be determined in well characterized rodent models of glomerular kidney disease using chronic dosing in conjunction with pharmacokinetic pharmacodynamic and safety studies PUBLIC HEALTH RELEVANCE Existing therapeutic approaches for treating chronic kidney disease CKD are inadequate in addressing patient needs and do not act directly target the kidney Our goal is to identify and develop a novel first in class therapeutic small molecule which is a functional antagonist of TRPC receptor channels Transient Receptor Potential Subfamily C member for the treatment of CKD Since TRPC is one of the most important signal integrators for the action of vasoactive hormones elevated glucose oxidative stress and mechanical stress on podocytes a TRPC antagonist will function as a drug directly targeting critical cells in the glomerulus that control filtration and thereby reduce proteinuria and slow th progression of CKD