Optimization of novel inhibitors of TRPC5 as anti-proteinuric therapeutics

描述（由申请方提供）：白蛋白尿是肾功能下降的单一最强预测因子，与心血管疾病的存在和严重程度相关，并可预测死亡率。足细胞功能障碍是肾小球疾病引起蛋白尿的罪魁祸首。足细胞TRPC 5信号传导在白蛋白尿发作中的作用表明了在进行性肾小球疾病如局灶节段性肾小球硬化症（FSGS）中的治疗益处，FSGS是具有不同病因的组织病理学诊断，包括基因突变、药物、病毒感染，并且最重要的是，作为代谢疾病如糖尿病、肥胖症和高血压的结果。目前，FSGS仍然是一种毁灭性的，基本上无法治愈的疾病，与发病率增加有关。我们以前已经证明，一种新的TRPC 4/5拮抗剂，ML 204，能够保护肾脏过滤器。然而，尚未鉴定出TRPC 5的高效和选择性拮抗剂。在这项提案中，我们将改进和优化我们的初始先导化合物ML 204，并测试其在啮齿动物疾病模型中减少蛋白尿的能力。为了开发这些一流的化合物，我们将利用迭代的药物化学方法和综合DMPK研究，这将使我们不仅能够评估效力和选择性，而且能够及时评估新制备化合物的体外和体内DMPK特性。这些选择性TRPC 5拮抗剂不仅提供了一个独特的机会来测试该提案中的假设，而且还有助于推动该领域的药物开发。

DESCRIPTION (provided by applicant): Albuminuria is the single strongest predictor of kidney function decline and is associated with the presence and severity of cardiovascular disease and predicts mortality. Dysfunction of podocytes is the major culprit of glomerular disease causing albuminuria. The demonstrated role of podocyte TRPC5 signaling in the onset of albuminuria suggests therapeutic benefit in progressive glomerular diseases such as Focal Segmental Glomerulosclerosis (FSGS), a histopathological diagnosis with different pathogeneses including genetic mutations, drugs, viral infections, and most importantly, as the result of metabolic disease, such as diabetes, obesity and hypertension. As it stands, FSGS remains a devastating and largely untreatable disease associated with increased morbidity. We have previously demonstrated that a novel TRPC4/5 antagonist, ML204, is able to protect the kidney filter. However, highly potent and selective antagonists of TRPC5 have not been identified yet. In this proposal, we will improve and optimize our initial lead compound, ML204, and test its ability to reduce proteinuria in rodent models of disease. In order to develop these first-in-class compounds, we will utilize an iterative medicinal chemistry approach and integrated DMPK studies which will allow us to evaluate not only potency and selectivity; but also the in vitro and in vivo DMPK properties of newly made compounds in a timely manner. These selective TRPC5 antagonists not only offer a unique opportunity to test the hypothesis in this proposal, but also, to help advance the field towards a drug development.