Treatment of pulmonary fibrosis with inhibitors of integrin alphavbeta1.

用整合素αvβ1抑制剂治疗肺纤维化。

基本信息

批准号：
8748498
负责人：
WILLIAM DEGRADO
金额：
$ 113.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8748498
关键词：
Affinity Animal Model Automobile Driving Back Binding Biological Assay Biological Availability Biological Markers Bleomycin Canis familiaris Cell surface Cells Characteristics Chemicals Clinical Trials Collagen Cutaneous Administration Development Diagnosis Disease model Dose Drug Kinetics Drug Targeting Drug or chemical Tissue Distribution Epithelial Cells Epithelium Evaluation Extracellular Matrix Fibroblasts Fibrosis Flow Cytometry Goals Grant Growth Factor Homeostasis Human In Vitro Integrins Label Lead Lung Mediating Modeling Modification Molecular Mus Normal tissue morphology Oral Paper Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Plasma Play Preparation Production Property Pulmonary Fibrosis Radiolabeled Rattus Risk Role Route Sampling Series Site Staging Structure of parenchyma of lung Surface Time Tissues Toxic effect Toxicology Transforming Growth Factor beta Transforming Growth Factors Treatment Efficacy analog design dosage drug candidate drug quality experience fluorophore humanized monoclonal antibodies improved in vitro Assay in vivo in vivo imaging inhibitor/antagonist man meetings mortality pharmacokinetic characteristic phase 1 study pre-clinical preclinical study prospective radiotracer receptor response scale up small molecule

Affinity Animal Model Automobile Driving Back Binding Biological Assay Biological Availability Biological Markers Bleomycin Canis familiaris Cell surface Cells Characteristics Chemicals Clinical Trials Collagen Cutaneous Administration Development Diagnosis Disease model Dose Drug Kinetics Drug Targeting Drug or chemical Tissue Distribution Epithelial Cells Epithelium Evaluation Extracellular Matrix Fibroblasts Fibrosis Flow Cytometry Goals Grant Growth Factor Homeostasis Human In Vitro Integrins Label Lead Lung Mediating Modeling Modification Molecular Mus Normal tissue morphology Oral Paper Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Plasma Play Preparation Production Property Pulmonary Fibrosis Radiolabeled Rattus Risk Role Route Sampling Series Site Staging Structure of parenchyma of lung Surface Time Tissues Toxic effect Toxicology Transforming Growth Factor beta Transforming Growth Factors Treatment Efficacy analog design dosage drug candidate drug quality experience fluorophore humanized monoclonal antibodies improved in vitro Assay in vivo in vivo imaging inhibitor/antagonist man meetings mortality pharmacokinetic characteristic phase 1 study pre-clinical preclinical study prospective radiotracer receptor response scale up small molecule

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项目摘要

DESCRIPTION (provided by applicant): Pulmonary fibrosis is a currently untreatable condition with a high mortality rate. One central common step in the development and progression of pulmonary fibrosis is the differentiation and expansion of pathologic fibroblasts that are largely responsible for the excess production of collagen and other extracellular matrix components that characterize tissue fibrosis. Transforming growth factor beta (TGF¿) is a critical driver of fibroblast differentiation and expansion. The applicants have identified a single integrin (¿v¿1) on the surface of fibroblasts that is responsible for fibroblast-mediated TGF¿ activation. They have taken advantage of extensive experience in developing integrin inhibitors to generate a small molecule that is the first potent and highly selective inhibitor of ¿v¿1 and have shown that this drug can inhibit bleomycin-induced pulmonary fibrosis when administered beginning 14 days after bleomycin, during the late fibrotic phase in this model. They now propose to chemically modify this lead compound to optimize its potency, bioavailability and tolerability, with the goal, in the first two years, of generating at least one lead drug that will be suitable fr oral or sub- cutaneous administration. Direct administration into the airways will be assessed, if necessary, as a back-up strategy. The applicants will also use labeled versions of lead compounds to assess the cell and tissue distribution of the target and develop assays for flow cytometry and potentially in vivo imaging. In the final 3 years of this two stage proposal the applicants will thoroughly evaluate the pharmacokinetics, stability, dose- response potency and toxicology of the most promising drug developed in the first two years, will scale up synthesis and generate GLP quality drug to perform 7 day and 28 day GLP- toxicity studies in rats and Beagle dogs to enable submission of an IND for first in man studies to the FDA. Because the results of this series of studies cannot be entirely predicted, the applicants will also continue a vigorous chemical modification, synthesis and evaluation pipeline to be sure that there are multiple additional promising candidates if the chosen lead compound fails at any step of the pre-clinical work-up. With this strategy there should be a high likelihood of generating an ¿v¿1-targeting drug suitable for clinical trials.

描述（由适用提供）：肺纤维化是目前无法治疗的情况，死亡率很高。肺纤维化发展和进展的一个核心共同步骤是病理纤维化的分化和扩展，这在很大程度上是导致胶原蛋白和其他细胞外基质成分的过量产生，这些成分表征了组织纤维化。转化生长因子β（TGF¿）是成纤维细胞分化和扩展的关键驱动力。申请人已经在成纤维细胞表面上鉴定了一个单一整合素（€»V¿1），该表面负责成纤维细胞介导的TGF激活。他们利用丰富的经验在开发整联蛋白抑制剂方面产生一个小分子，该分子是第一个潜力和高度选择性抑制剂。现在，他们建议对这种铅化合物进行化学修改，以优化其效力，生物利用度和耐受性，而在头两年中，目标是生成至少一种铅药物，该药物将是合适的口服或皮肤皮肤给药。如有必要，将直接管理到航空公司作为备用策略。应用还将使用标记的铅化合物版本来评估靶标的细胞和组织分布，并开发流式细胞仪的评估，并可能在体内成像。 In the final 3 years of this two stage proposal the applications will thoroughly evaluate the pharmacokinetics, stability, dose-response potency and toxicology of the most promising drug developed in the first Two years, will scale up synthesis and generate GLP quality drug to perform 7 days and 28 days GLP-toxicity studies in rats and Beagle dogs to enable submission of an IND for first in man studies to the FDA.由于无法完全预测这一系列研究的结果，因此申请人也将继续如果所选的铅化合物在临床前检查的任何步骤中失败，则剧烈的化学修饰，合成和评估管道可以确保有多个额外的承诺。通过这种策略，应该很有可能产生适合临床试验的1靶向药物。