Optimization of novel inhibitors of TRPC5 as anti-proteinuric therapeutics

描述（由申请人提供）：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，并预测死亡率。足细胞功能障碍是引起蛋白尿的肾小球疾病的罪魁祸首。足细胞TRPC5信号在蛋白尿发病中的作用表明，在进展性肾小球疾病（如局灶节段性肾小球硬化（FSGS））中有治疗价值，FSGS是一种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，最重要的是，它是代谢性疾病（如糖尿病、肥胖和高血压）的结果。就目前而言，FSGS仍然是一种具有破坏性且在很大程度上无法治愈的疾病，其发病率也在增加。我们之前已经证明了一种新的TRPC4/5拮抗剂ML204能够保护肾脏过滤器。然而，TRPC5的高效和选择性拮抗剂尚未被发现。在本提案中，我们将改进和优化我们的初始先导化合物ML204，并在啮齿动物疾病模型中测试其减少蛋白尿的能力。为了开发这些一流的化合物，我们将利用迭代药物化学方法和整合的DMPK研究，这将使我们不仅能够评估效力和选择性；还可以及时了解新合成化合物的体内和体外DMPK特性。这些选择性TRPC5拮抗剂不仅提供了一个独特的机会来测试本提案中的假设，而且还有助于推进该领域的药物开发。

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.