Development of a small molecule inhibitor of PAI-1 for the treatment of diffuse cutaneous systemic sclerosis

开发用于治疗弥漫性皮肤系统性硬化症的 PAI-1 小分子抑制剂

基本信息

批准号：
9619126
负责人：
James Craig Hartman
金额：
$ 21.68万
依托单位：
MDI THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9619126
关键词：
Affect Alzheimer&apos s Disease Biological Markers Cessation of life Clinical Cutaneous Data Development Diffuse Disease Dose Drug Kinetics Drug Targeting Etiology Family Fibrinolysis Fibrosis Goals Heart Diseases In Vitro Interstitial Lung Diseases Kidney Diseases Lead Lung diseases Modeling Mus Oral Organ Pathology Patients Pharmaceutical Preparations Pharmacology Phase Physiological Physiology Pirfenidone Plasma Plasminogen Activator Inhibitor 1 Process Property Protease Inhibitor Pulmonary Fibrosis Research Safety Scleroderma Series Serine Proteinase Inhibitors Serpins Small Business Innovation Research Grant Specificity Systemic Scleroderma Therapeutic Tissues Toxicology Urokinase Vitronectin Wound Healing clinical candidate commercialization comparative efficacy drug candidate drug discovery experimental study high throughput screening human disease in vivo in vivo Model inhibitor/antagonist innovation interest man member mortality mouse model novel novel therapeutics phase 1 study pre-clinical preclinical study prevent programs screening small molecule small molecule inhibitor success therapeutic target

项目摘要

This project will provide critical preclinical data for a novel therapeutic small molecule inhibitor of plasminogen activator inhibitor 1 (PAI-1) as a potential treatment for diffuse cutaneous systemic sclerosis with associated interstitial lung disease (dcSSc-ILD). SSc is a devastating disease of unknown etiology with no currently approved disease-modifying treatments; lung fibrosis (interstitial lung disease, ILD) is the leading cause of mortality in dcSSc. In this application we will assess the clinical utility of a highly innovative first in class therapeutic. PAI-1 is the physiologic inhibitor of tissue and urokinase plasminogen activator (tPA and uPA). In normal physiology PAI-1 regulates processes such as fibrinolysis and wound healing. However, elevated expression of PAI-1 is associated with fibrotic diseases of the lung, kidney, heart, and importantly for this application, with SSc. This association has led to the recognition that PAI-1 contributes directly to pathology, and that its inhibition may be an effective approach to treat fibrotic disease. MDI Therapeutics has identified a series of highly effective, orally active, small molecule inhibitors of PAI-1 with efficacy in multiple models of fibrotic disease, including pulmonary fibrosis and SSc. The studies described in this Phase 1 application will compare the two top candidate molecules in this series, MDI-2268 and MDI-2517, with the primary goal of selecting the clinical candidate molecule for the IND-enabling studies that will be performed in Phase 2 of this SBIR. There are two specific aims with clear milestones that will effectively assess the clinical utility of these highly innovative first in class therapeutics. These milestones include comparing the two clinical candidates for efficacy in a murine model of SSc relative to the current treatment options; direct comparison of their pharmacokinetics properties, and their safety in 7 day multi-dose toxicology studies. The successful completion of these milestones will significantly advance this program toward commercialization by identifying a single lead clinical candidate to be selected for API synthesis and for the IND-enabling toxicology studies planned in Phase 2 of this SBIR.

该项目将为新型的纤溶酶原治疗小分子抑制剂提供关键的临床前数据激活剂抑制剂1（PAI-1）作为弥漫性皮肤硬化性硬化症的潜在治疗方法间质性肺疾病（DCSSC-ILD）。 SSC是一种毁灭性的病因，目前没有批准的疾病改良治疗；肺纤维化（间质性肺病，ILD）是 DCSSC的死亡率。在此应用程序中，我们将评估一流的高度创新性的临床实用性治疗性。 PAI-1是组织和尿激酶纤溶酶原激活剂（TPA和UPA）的生理抑制剂。在正常生理PAI-1调节纤维蛋白溶解和伤口愈合等过程。但是，抬高了 PAI-1的表达与肺，肾脏，心脏的纤维化疾病有关，并且重要的是应用，SSC。该关联已导致人们认识到PAI-1直接促进了病理学，并且其抑制作用可能是治疗纤维化疾病的有效方法。 MDI Therapeutics已确定 PAI-1的一系列高效，口服的小分子抑制剂在多种模型中具有功效纤维化疾病，包括肺纤维化和SSC。该阶段1应用中描述的研究将比较本系列中的两个顶级候选分子MDI-2268和MDI-2517，主要目标是选择将在此阶段第二阶段进行的临床候选分子进行辅助研究 Sbir。有两个具体的目标具有明确的里程碑，可以有效地评估这些临床实用性高度创新的课堂治疗学。这些里程碑包括比较两个临床候选者相对于当前的治疗选择，SSC的鼠模型的功效；直接比较他们药代动力学特性及其在7天多剂量毒理学研究中的安全性。成功完成这些里程碑将通过确定一个单一的里程铅临床候选者被选为API合成以及计划在计划中的毒理学研究此SBIR的第2阶段。