NOVEL AGENTS TO PREVENT KIDNEY DISEASE IN DIABETES

该项目的目标是开发一种具有抗糖基化特性的小分子，并适用于糖尿病肾病的治疗。第一阶段的主要目标是：a)设计和合成EXO-226的结构类似物；b)测试新合成的化合物抑制白蛋白非酶糖基化的能力。这项工作的基本原理源于我们最近的研究表明：a)糖化白蛋白刺激细胞外基质蛋白（ECM）、tgf - β 1和II型tgf - β受体的表达，并激活肾小球细胞的PKC；b)在未治疗的糖尿病小鼠中观察到，给药与Amadori葡萄糖加合物修饰的白蛋白位点特异性反应的小鼠单克隆抗体，可以减少尿蛋白排泄升高，抑制系膜基质积聚，并防止肾IV型胶原和纤维连接蛋白mRNA的过度表达；C)这些有益作用与血浆糖化白蛋白浓度升高的降低有关（即使明显的高血糖持续存在）；d) EXO- 226在体外、体内（db/db小鼠和人）抑制糖化白蛋白的形成，即使血糖浓度仍然升高；e)用EXO-226降低糖化白蛋白与人类尿白蛋白排泄减少有关，并与改善db/db小鼠糖尿病肾病的结构和功能变化有关（即，它降低尿蛋白排泄升高，提高肌酐清除率降低，减轻肾小球系膜基质的积累）。II期的主要目标是在I期结果的基础上进行临床前、动物和毒理学研究，以表明所选化合物是安全有效的，从而启动新药实体的人体临床试验。拟议的商业应用：这项研究和开发有望导致预防/治疗糖尿病肾病的新化学实体的临床引入。

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. PROPOSED COMMERCIAL APPLICATION: This research and development is expected to lead to the clinical introduction of new chemical entities for the prevention/treatment of diabetic kidney disease.