NOVEL AGENTS TO PREVENT KIDNEY DISEASE IN DIABETES

描述（改编自申请）：项目的目标

DESCRIPTION (Adapted from the application): The objective of the project is to synthesize and develop a small molecule that possesses anti- glycation properties and that is appropriate for therapeutic use in diabetic nephropathy. The major goal in Phase I is to synthesize analogs of a compound in the heteroaryl acetic acid class and to test their ability to inhibit the non-enzymatic glycation of albumin. The rationale for the work derives the investigators recent studies that demonstrated that glycated albumin induces expression of collagen, fibronectin, and TGF-beta in renal glomerular mesangial cells; administration of monoclonal antibodies against modified albumin reduce elevated urinary protein excretion, inhibits mesangial matrix accumulation, and prevents the over- expression of the molecular components; these effects are associated with a reduction of elevated plasma glycated albumin despite the fact that hyperglycemia persists; a small molecule designated EX0-226, inhibits the formation of glycated albumin in vitro and in vivo; and a significant reduction in urine protein excretion accompanies the decrease in plasma glycated albumin. In Phase I the investigator will synthesize and systematically test analogs of this compound that have been designed to retain and optimize anti-glycated properties, and minimize or eliminate cyclooxygenase inhibitory activities which are associated with undesirable side effects. PROPOSED COMMERCIAL APPLICATION: Proposed commercial application not available.