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.
Pulmonary fibrosis is a currently untreatable condition with an estimated 50% mortality within 3 years of diagnosis. The co-PIs of this application have identified a very promising and specific lead compound that is highly effective in an animal model of pulmonary fibrosis. This proposal will improve this compound to make it an effective drug and perform the pre-clinical studies required to develop this drug for clinical trials..