Novel and Kidney Selective AMPK Activators to Treat Polycystic Kidney Disease

DESCRIPTION provided by applicant Autosomal dominant polycystic kidney disease ADPKD is characterized by the presence of innumerous fluid filled cysts that progressively enlarge leading nephron loss and the progressive decline in renal function Aberrant proliferation of the cyst lining epithelial cells and the accumulation of fluid within the cysts du to Cl dependent fluid secretion are responsible for the growth of the cysts During the past fifteen years there has been enormous amounts information gained from PKD research however there is still a lack of understanding on how to effectively treat the disease Tolvaptan a vasopressin V receptor antagonist was highly effective in animals models of PKD and significantly slow PKD progression in patients of the TEMPO trial however the drug caused liver complications is some patients and was not approved by the FDA for treatment of PKD mTOR inhibitors such as rapamycin are also being considered as potential disease modifying therapies however clinical trials of these agents have been disappointing One concern is that circulating concentrations of the drug at concentrations that are tolerated relatively well may not be sufficient to inhibit mTOR in the kidneys Recently folate conjugated rapamycin was shown to specifically target the kidney since the pro drug was taken up by the folate receptor mediated endocytosis and cleaved releasing the active rapamycin within the kidney cells NovaTarg in collaboration with the Kidney Institute at the University of Kansas Medical Center has identified an innovative approach to inhibit cyst growth Taking advantage of the focused medicinal chemistry program at NovaTarg and the expertise of the PKD investigators at KUMC we have developed kidney specific AMPK activators that inhibit ADPKD cell proliferation through p and the mTOR pathway and fluid secretion driven by CFTR mediated Cl secretion Our approach is based on the synthesis of novel biguanides analogues of metformin that utilize the kidney specific organic cation transporter OCT to enter kidney cells and to activate AMPK in the cyst lining cells Biguanides are very basic compounds which require OCTs for cellular entry but metformin itself does not discriminate between OCT liver and OCT kidney An important complication of the use of metformin in patients with chronic kidney disease is the development of lactic acidosis due to the accumulation of the drug in the liver Thus NovaTarg has synthesized andgt biguanide analogues of metformin to identify biguanides that are selectively transported by OCT to target kidney cells An early lead compound NT activated AMPK in human ADPKD cells leading to inhibition of mTOR mediated cell proliferation and transepithelial Cl secretion In addition NT blocked in vitro cyst formation of ADPKD cells cultured within a collagen matrix and the expansion of cyst like structures in Pkd mouse embryo kidneys ex vivo We think that highly OCT selective biguanides will avoid liver uptake by OCT and display the safety profile required for this population of patients During Phase of the SBIR NovaTarg discovered a highly OCT selective biguanide NT that has higher selectivity for OCT than NT but is not quite as potent In Phase we will synthesis derivatives of NT for hit to lead optimization and evaluate the drug in preclinical studies and prepare for testing the drug is a proof of principal clinical trial PUBLIC HEALTH RELEVANCE Autosomal dominant polycystic kidney disease is a life threatening condition affecting million people worldwide for which there are no treatments Approximately half of the patients progress to end stage renal disease ESRD by the sixth decade of life The medical and economic costs of ADPKD are considerable PKD is responsible for of all patients requiring renal transplantation and dialysis costing andgt $ B year in the US alone NovaTarg has discovered a novel kidney selective treatment that offers the possibility of disease modifying drug therapy for PKD