Research Project
8000773
DESCRIPTION (provided by applicant): Asthma is a very common lung condition in children, and incidence is increasing in the US particularly in urban and minority populations. The standard of care for asthmatics is inhaled steroid, although clinical response is variable. The mechanism of efficacy of steroids in asthma is thought to be via anti-inflammatory pathways, although other anti-inflammatory drugs have generally shown poor efficacy. Here, we describe a new series of drugs that show promise in the treatment of asthma symptoms. The VBP series shows lack of competitive binding to the glucocorticoid receptor, yet retains strong transrepression (signaling) activities of glucocorticoids indicative of a dissociation of glucocorticoid sub-activities (transcriptional vs. signaling) which is hypothesized to maintain the beneficial effects while reducing the metabolic side effects of tradition steroid therapies (e.g. prednisone). We present preliminary data showing that Dexamethasone resynchronizes the cell cycle of asthmatic primary differentiated bronchial epithelial cells and dramatically reduces cytokine production from these cells. VBP drugs retain the ability of glucocorticoids to resynchronize the cell cycle in these same primary bronchial cells. We show extensive data on NF-(B transactivation in muscle cells, where VBP drugs retain potency in NF-(B inhibition, similar to prednisone. This STTR application is to characterize 20 VBP derivatives in lung-derived cells with regards to NF-(B inhibition, cell cycle synchronization, and cytokine production. The deliverable is to identify lead compounds from the 20 that will be taken into in vivo testing in asthmatic mouse models, and subsequent toxicology and clinical trials. PUBLIC HEALTH RELEVANCE: Synthetic glucocorticoids are a standard treatment for Asthma. Asthma has become considerably more prevalent and severe in the United States during the last 30 years with approximately 83 in 1,000 children affected. The greater efficacy of synthetic glucocorticoids has made them the standard anti-inflammatory therapy for the treatment of asthma for decades. However, there is a subset of patients that do not respond to steroid therapies in addition to the side effects of chronic use of steroids for those patients that are responsive. The aim of this study is to perform in vitro screening of newly developed non-hormonal steroids for the treatment of asthma. The 5 most optimal compounds will be tested in an ex vivo model with the goal of identifying 2-3 lead compounds to take into the mouse model for asthma.
