Treatment of pulmonary fibrosis with inhibitors of integrin alphavbeta1.

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。病理成纤维细胞的分化和扩张是肺纤维化发生和发展的一个共同的中心步骤。病理性成纤维细胞的分化和扩张在很大程度上导致了组织纤维化特征的胶原蛋白和其他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子。申请人已经在成纤维细胞表面发现了一个单一的整合素（v 1），该整合素负责成纤维细胞介导的TGF激活。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，这是第一种强效和高选择性的v 1抑制剂，并表明该药物可以抑制博莱霉素诱导的肺纤维化，当在博莱霉素后14天开始施用时，在该模型的纤维化晚期。他们现在提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。如果有必要，将评估直接进入气道的管理，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目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。在这两阶段提案的最后3年，申请人将彻底评估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，将扩大合成并产生GLP质量药物，在大鼠和Beagle犬中进行7天和28天的GLP毒性研究，以便向FDA提交首次人体研究的IND。由于这一系列研究的结果不能完全预测，申请人还将继续

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.