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的疾病，死亡率高。肺纤维化的发展和进展中的一个中心共同步骤是病理性成纤维细胞的分化和扩增，病理性成纤维细胞在很大程度上负责胶原蛋白和表征组织纤维化的其他细胞外基质组分的过量产生。转化生长因子β（TGF β）是成纤维细胞分化和扩增的关键驱动因素。申请人已经鉴定了成纤维细胞表面上负责成纤维细胞介导的TGF β活化的单个整合素（β v β 1）。他们利用在开发整合素抑制剂方面的丰富经验，产生了一种小分子，这是第一种有效的和高选择性的抑制剂，并表明这种药物可以抑制博莱霉素诱导的肺纤维化，当博莱霉素后14天开始给药时，在该模型的晚期纤维化阶段。他们现在提出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，将评估气道直接给药作为备用策略。申请人还将使用标记形式的先导化合物来评估靶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测定。在该两阶段提案的最后3年，申请人将全面评价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，将扩大合成并生产GLP质量药物，以在大鼠和比格犬中进行7天和28天GLP毒性研究，从而能够向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一项 严格的化学修饰、合成和评估管道，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，则存在多个额外的有希望的候选物。通过这种策略，应该有很高的可能性产生适合临床试验的靶向药物。