Treatment of pulmonary fibrosis with inhibitors of integrin alphavbeta1.

用整合素αvβ1抑制剂治疗肺纤维化。

• 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
• 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

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且死亡率很高的疾病。肺纤维化发生和进展的一个核心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和其他表征组织纤维化的细胞外基质成分的过量产生。转化生长因子β (TGF¿) 是成纤维细胞分化和扩张的关键驱动因素。申请人已经鉴定出成纤维细胞表面上的单个整联蛋白（“v”1）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，生成了一种小分子，这是第一个有效且高度选择性的 ¿v¿1 抑制剂，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，该药物可以抑制博来霉素诱导的肺纤维化。他们现在建议对这种先导化合物进行化学修饰，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。如有必要，将评估对气道的直接给药，作为备用策略。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，并开发流式细胞术和潜在的体内成像分析方法。在这个两阶段提案的最后3年中，申请人将彻底评估前两年开发的最有前途的药物的药代动力学、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，以在大鼠和Beagle犬中进行7天和28天的GLP毒性研究，以便能够向FDA提交首次人体研究的IND。由于这一系列研究的结果无法完全预测，申请人还将继续进行 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，还有多种其他有希望的候选药物。通过这种策略，应该很有可能产生适合临床试验的 ¿v¿1 靶向药物。