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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.

该项目将为一种新的治疗性小分子纤溶酶原抑制剂提供关键的临床前数据。激活物抑制物1(PAI-1)对弥漫性皮肤系统性硬化症的潜在治疗作用间质性肺疾病(dcSSc-ILD)。SSc是一种病因不明的破坏性疾病，目前尚无批准的疾病修正治疗；肺纤维化(间质性肺病)是 Dcssc死亡率。在这项应用中，我们将评估一流的高度创新的临床应用有治疗作用。PAI-1是组织生理性抑制物和尿激酶型纤溶酶原激活物(tPA和uPA)。在……里面正常生理状态下，PAI-1调节纤溶和伤口愈合等过程。但是，提升了 PAI-1的表达与肺、肾、心脏的纤维化疾病有关，对此很重要应用程序，带有SSC。这种联系导致了对PAI-1直接参与病理的认识，它的抑制作用可能是治疗纤维化疾病的有效方法。MDI治疗公司已经确定了一种一系列高效、口服活性的PAI-1小分子抑制剂，在多种模型中有效纤维化疾病，包括肺纤维化和SSc。此阶段1应用程序中描述的研究将比较本系列中排名靠前的两个候选分子MDI-2268和MDI-2517，主要目标是为IND使能研究选择临床候选分子，该研究将在本研究的第二阶段进行 SBIR。有两个具有明确里程碑的具体目标将有效地评估这些药物的临床效用。极具创新性的一流治疗学。这些里程碑包括比较两个临床候选对象在SSc小鼠模型中相对于当前治疗方案的疗效； 7天多剂量毒理学研究中的药代动力学特性及其安全性。圆满完成这些里程碑中的一个将极大地推动该项目走向商业化，通过确定一个主要临床候选人将被选为原料药合成和计划于#年进行的IND毒理学研究此SBIR的第二阶段。