There nearly 24 million people in the U.S. who suffer from diabetes and who are at risk for diabetic retinopathy (DR), a vascular complication of diabetes that is the leading cause of blindness in working age adults. A major cause of vision loss in DR is increased retinal vascular permeability (RVP), leading to a build-up of fluid in the macula, a debilitating clinical condition known as diabetic macular edema (DME). We show by multiple lines of evidence that the serine protease plasma kallikrein (PK) is involved in the increased RVP in animal models of diabetes and hypertension. When delivered subcutaneously, PK inhibitors developed as part of our phase 1 grant effectively inhibit RVP in animal models of hypertension. PK inhibitors with oral bioavailability, however, would be preferred for chronic and long term administration to diabetics. The goal of this phase II grant is to develop a safe, effective and orally-available PK inhibitor for the chronic, long term treatment of DME in DR. We will specifically focus on our current series of PK inhibitors that have promise for oral bioavailability and are amenable to chemical changes that are proven to increase oral bioavailability. The inhibitors will be tested for their ability to block RVP in hypertensive and diabetic animals when given orally at moderate daily doses. The safety and potential """"""""off-target"""""""" effects of the efficacious compounds will subsequently be determined so as to identify an orally-available compound with a sufficient safety margin that can be considered for further preclinical development and IND-enabling toxicology studies.
This Phase II project proposes that inhibition of the serine protease plasma kallikrein (PK), would have significant therapeutic impact in reducing diabetic macular edema (DME) in diabetic retinopathy (DR). It seeks to optimize a lead series of small molecule inhibitors of PK to obtain orally available lead molecules for testing in animal models of diabetes- and hypertension-induced retinal vascular permeability, followed by initial evaluation of the potential safety margin for the lead molecule in a repeat-dose acute toxicology study.
