DESCRIPTION (provided by applicant): This Phase II project will conduct animal toxicology and pharmacokinetics and will initiate clinical evaluation of 22CPPA, a novel pharmacological agent for the prevention/treatment of diabetic glomerulosclerosis. The rationale for this project derives from our work encompassing in vitro and in vivo studies that have established that: a) Amadori-modified glycated albumin (GA) induces significant alterations in glomerular cell biology that are highly reminiscent of the in vivo features of diabetic nephropathy; b) these effects resemble, but operate independent of, those induced by high glucose concentrations and are observed with concentrations of the glycated protein that are found in clinical specimens; c) GA stimulates glomerular production of TGF-beta1 and its type II signaling receptor and activates glomerular PKC-beta and ERK; d) 22CPPA inhibits the condensation of glucose with reactive amino groups in albumin and significantly lowers serum concentrations of GA in hyperglycemic, diabetic animals; and e) in vivo inhibition of the nonenzymatic glycation of albumin by 22CPPA reduces glomerular over-expression of TGF-beta1, and prevents glomerulosclerosis and renal insufficiency even when hyperglycemia prevails. Based on these findings, we have proposed that targeting the over-expression of glomerular TGF-beta1 through inhibiting the excess nonenzymatic glycation of albumin in diabetes is a viable therapeutic strategy for preventing the progression of diabetic glomerulosclerosis and that 22CPPA is a novel clinical candidate for treatment of this morbid complication of diabetes. The Phase I goals of this project, which have been accomplished, were to delineate the dose-response profile of 22CPPA on the therapeutic targets, to examine its acute lethality/toxicity, and to initiate process development in preparation for GMP manufacture of clinical grade compound to be used in the Phase II portions of this project. The Specific Aims of the Phase II project are to: 1) Obtain and complete analytical testing procedures/validation of process developed drug substance and of GMP lot of 22CPPA; 2) Conduct pharmacokinetic and biodistribution profiling and 3) in vitro genetic toxicology testing of 22CPPA; 4) Perform subacute/chronic formal animal toxicology with GMP-manufactured 22CPPA to support human clinical Phase I safety, metabolism and pharmacokinetic studies (4 week animal tox.) and clinical Phase IIA (12 week animal tox.) trials in human subjects; 5) Submit an Investigational New Drug application to the FDA; 6) Complete Phase I clinical safety studies in normal healthy human volunteers (single rising dose and multiple rising dose), according to protocols submitted to and approved by the FDA; 7) Perform short-term Phase IIA clinical studies in target (diabetic) population, monitoring safety and evaluating efficacy with surrogate markers, according to protocols submitted to and approved by the FDA; 8) Present results to prospective commercialization partners.