LPA Antagonists for the Treatment of IPF

描述（由申请人提供）：特发性肺纤维化（IPF）是一种进行性、痛苦性、衰弱性和常规致命性疾病，在美国有20万人受到折磨。 美国和全世界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。虽然IPF的病因目前尚不清楚，但认为各种损伤破坏了炎症与肺组织修复之间的紧密调节，导致成纤维细胞过度产生胶原蛋白并形成过多的瘢痕组织，从而不可逆地破坏肺结构和功能。溶血磷脂酸（LPA）信号传导在IPF中的作用已得到明确确立;通过G蛋白偶联的LPA 1受体，LPA介导成纤维细胞募集到肺纤维化中，从而超加速正常修复过程，导致纤维化。选择性LPA 1受体拮抗剂可以干预失调的炎症/修复周期，预防纤维化，并使受影响的个体受益。我们的长期目标是开发LPA 1受体的小分子拮抗剂作为IPF的潜在治疗药物。本申请的目的是鉴定此类拮抗剂并在两种临床相关的IPF动物模型中对其进行评价。 公共卫生相关性：小分子LPA 1拮抗剂是特发性肺纤维化（IPF）的潜在治疗药物。

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).