Selective LPA1 receptor antagonists as agents in prevention of renal fibrosis

描述(由申请人提供)：我们项目的最终目标是开发对慢性肾脏疾病有效的新疗法，这些疾病通常会发展为纤维化，导致终末期肾脏疾病，需要肾脏替代疗法。这将通过寻找新的溶血磷脂酸(LPA)1型受体的选择性功能拮抗剂来实现。我们的药物发现方法将合成没有药物相互作用风险的新化合物，这些化合物表明LPA-1受体具有选择性的功能拮抗作用。它们的有效性将通过一系列基于高通量细胞的分析来证实。然后将评估候选分子在单侧输尿管梗阻(UUO)动物模型中预防肾纤维化进展的能力。这项第一阶段研究的目的是确定至少一个新的分子系列，用于第二阶段计划中的先导优化。 公共卫生相关性：目标是发现和开发治疗慢性肾脏疾病的新药，这些疾病涉及肾脏纤维化，肾脏纤维化是导致死亡的一个重要原因。

DESCRIPTION (provided by applicant): The ultimate goal of our project is to develop novel therapeutics effective in chronic kidney diseases that normally develop fibrosis, lead to end stage renal disease and require renal replacement therapy. This will be achieved by identifying novel selective functional antagonists for the lysophosphatidic acid (LPA) type 1 receptor. Our drug discovery approach will synthesize novel compounds free of drug-drug interaction risks that demonstrate selective, functional antagonism of the LPA-1 receptor. Their effectiveness will be confirmed using a series of high throughput cell-based assays. Candidate molecules will then be evaluated for their ability to prevent the progression of renal fibrosis in a unilateral ureteral obstruction (UUO) animal model. The intent of this Phase 1 study is to identify at least one novel series of molecules for lead optimization in a Phase 2 program. PUBLIC HEALTH RELEVANCE: The objective is to discover and develop new drugs for treating chronic kidney diseases that involve renal fibrosis, a significant cause of mortality.