LPA Antagonists for the Treatment of IPF

描述(申请人提供)：特发性肺纤维化(IPF)是一种进行性的、令人痛苦的、衰弱的、通常是致命的疾病，在美国有20万人受到困扰 美国和世界各地的500万患者。目前还没有有效的治疗方法来治疗这种毁灭性的疾病。尽管IPF的病因目前尚不清楚，但各种侮辱被认为破坏了肺组织炎症和修复之间的紧密调控，导致成纤维细胞过度产生胶原，形成过度的瘢痕组织，不可逆转地破坏肺结构和功能。溶血磷脂酸(LPA)信号在IPF中的作用已得到证实；通过G蛋白偶联的LPA1受体，LPA介导成纤维细胞重新聚集到肺间质，从而加速正常的修复过程，导致纤维化。一种选择性的LPA1受体拮抗剂可以干预失调的炎症/修复周期，防止纤维化，并使患者受益。我们的长期目标是开发LPA1受体的小分子拮抗剂，作为治疗IPF的潜在药物。这项应用的目的是鉴定这种拮抗剂，并在两种临床相关的IPF动物模型中对它们进行评估。 公共卫生相关性：小分子LPA1拮抗剂是治疗特发性肺纤维化(IPF)的潜在药物。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a progressive, agonizing, debilitating and routinely fatal disease that afflicts 200,000 individuals in the United States and five million patients worldwide. There are currently no effective treatments available for this devastating illness. Although the etiology of IPF is currently unknown, various insults ar thought to disrupt the tight regulation between inflammation and repair of lung tissue leading to excess production of collagen by fibroblasts and the formation of excessive scar tissue, irreversibly destroying lung structure and function. The role of lysophosphatidic acid (LPA) signaling in IPF has been firmly established; through a G protein-coupled LPA1 receptor, LPA mediates recruitment of fibroblasts into the pulmonary interstitium which hyper-accelerates normal repair processes, resulting in fibrosis. A selective LPA1 receptor antagonist may intervene in the dysregulated inflammation/repair cycle, prevent fibrosis, and benefit afflicted individuals. Our long-term goal is to develop small molecule antagonists of the LPA1 receptor as potential therapeutics for IPF. The objective of this application is to identify such antagonists and evaluate them in two clinically relevant animal models of IPF. PUBLIC HEALTH RELEVANCE: Small molecule LPA1 antagonists are potential therapeutics for idiopathic pulmonary fibrosis (IPF).