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：
8931040
负责人：
WILLIAM DEGRADO
金额：
$ 102.52万
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 2016-07-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8931040
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

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（由申请人提供）：肺纤维化是一种目前无法治疗的高死亡率疾病，肺纤维化发生和进展的一个主要共同步骤是病理性成纤维细胞的分化和扩张，这在很大程度上导致了胶原蛋白的过量产生。以及其他表征组织纤维化的细胞外基质成分是成纤维细胞分化和扩张的关键驱动因素。 (v�1) 位于成纤维细胞表面，负责成纤维细胞介导的 TGF� 激活。他们利用开发整合素抑制剂的丰富经验，生成了第一个有效且高度选择性的 �v 抑制剂。 �1 并表明，在该模型的纤维化晚期阶段，在博莱霉素注射后 14 天开始给药时，该药物可以抑制博莱霉素诱导的肺纤维化。他们现在建议对此进行化学修饰。将评估先导化合物，以优化其效力、生物利用度和耐受性，目标是在头两年内产生至少一种适合口服或皮下给药的先导药物。必要时，作为后备策略，申请人还将使用先导化合物的标记版本来评估靶标的细胞和组织分布，并在这两个阶段的最后 3 年中开发流式细胞术和潜在的体内成像分析方法。申请人将彻底评估提案头两年开发的最有前途药物的药代动力学、稳定性、剂量反应效力和毒理学，将扩大合成规模并产生 GLP 优质药物，在大鼠和比格犬中进行 7 天和 28 天的 GLP 毒性研究，以便能够提交由于这一系列研究的结果无法完全预测，申请人还将继续向 FDA 提交首次人体研究的 IND 申请。强有力的化学修饰、合成和评估流程，以确保如果所选的先导化合物在临床前检查的任何步骤失败，则有很高的可能性产生潜在的候选化合物。 �1个适合临床试验的靶向药物。