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(申请人提供)：肺纤维化是一种目前无法治疗的疾病，死亡率很高。在肺纤维化的发展和进展中，一个重要的共同步骤是病理性成纤维细胞的分化和扩张，这些成纤维细胞在很大程度上导致胶原和其他细胞外基质成分的过度产生，这些成分是组织纤维化的特征。转化生长因子β是成纤维细胞分化和扩增的关键驱动力。申请人已经确定了成纤维细胞表面的单一整合素，负责成纤维细胞介导的转化生长因子的激活。他们利用在开发整合素抑制剂方面的广泛经验来产生一种小分子，这是第一个有效的和高选择性的V1抑制剂，并表明这种药物在博莱霉素后14天开始给药时可以抑制博莱霉素诱导的肺纤维化，在这个模型的纤维化后期。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，将评估直接对航空公司进行管理，作为一种后备战略。申请者还将使用标记的先导化合物版本来评估目标的细胞和组织分布，并开发用于流式细胞术和潜在的体内成像的分析方法。在这两个阶段的提案的最后三年，申请者将彻底评估在前两年开发的最有希望的药物的药代动力学、稳定性、剂量反应效力和毒理学，将扩大合成规模并生产GLP优质药物，在大鼠和Beagle狗身上进行7天和28天的GLP毒性研究，以便向FDA提交IND首个人类研究。由于这一系列研究的结果不能完全预测，申请者还将继续 积极的化学修饰、合成和评估流程，以确保如果所选的先导化合物在临床前工作的任何步骤失败，都会有多个额外的有希望的候选者。有了这一策略，应该很有可能产生一种适合临床试验的靶向药物。