The objective of this project is to develop a small molecule that possesses anti-glycation properties and that is appropriate for therapeutic use in diabetic nephropathy. The major goals in Phase I, which have been accomplished, were to: a) design and synthesize structural analogues of EXO-226; and b) test the newly synthesized compounds for their ability the inhibit the nonenzymatic glycation of albumin. The rationale for this work derives from our recent studies demonstrating that: a) glycated albumin stimulates the expression of extracellular matrix proteins (ECM), TGF-beta1 and the signaling Type II TGF-beta receptor, and activates PKC, in renal glomerular cells; b) administration of a murine monoclonal antibody that site- specifically reacts with albumin modified by Amadori glucose adducts to diabetic db/db mice reduces the elevated urinary protein excretion, inhibits the mesangial matrix accomulation, and prevents the overexpression of renal Type IV collagen and fibronectin mRNA that are observed in untreated diabetic mice; c) these salutary effects are associated with reduction of elevated plasma glycated albumin concentrations (even though marked hyperglycemia persists); d) EXO- 226 inhibits the formation of glycated albumin in vitro, and in vivo in the db/db mouse and in man, even though blood glucose concentrations remain elevated; and e) lowering glycated albumin with EXO-226 is associated with reduced urine albumin excretion in man, and with amelioration of the structural and functional changes of diabetic nephropathy in the db/db mouse (i.e. it reduces the elevated urine protein excretion, raises the decreased creatinine clearance, and attenuates the accumulation of glomerular mesangial matrix). The major goals in Phase II are to conduct, with the clinical condidate(s) selected on the basis of Phase I results, preclinical, animal and toxicology studies to show that the selected compound is safe and effective, leading to initiation of human clinical trials with the new drug entity.
This research and development is expected to lead to the clinical introduction of new chemical entities for the prevention/treatment of diabetic kidney disease.
