Bronchopulmonary Dysplasia Drug Therapy

DESCRIPTION (provided by applicant): Neutrophils are bloodborne inflammatory cells that exhibit potent oxidative and phagocytic activities. One important component of the neutrophils' role in the immune system is its ability to migrate rapidly towards sites of inflammation in a process known as chemotaxis. Chemotaxis is mediated through numerous chemotactic factors that include IL-8 and Gro-alpha interacting with the neutrophil receptors CXCR1 and CXCR2. Improper and heightened neutrophil recruitment is a hallmark of several inflammatory diseases that include bronchopulmonary dysplasia in neonates subjected to mechanical ventilation with supplemental oxygen. We are developing a potent series of novel and proprietary chemotaxis inhibitors known as the nicotinamide thioglycolate esters to treat bronchopulmonary dysplasia. While initial screening identified several nicotinamide thioglycolate esters that potently inhibited chemotaxis (IC50 < 40 nM), their mechanism of inhibition is enigmatic. To further advance this promising therapeutic class, additional research is required to define their exact mechanism of action. This Phase I/II Fast-Track proposal is aimed at defining the pharmacology and pharmaceutics of these novel chemotaxis inhibitors. In Phase I, we aim to identify whether the site of action is at CXCR1 and/or CXCR2, or less likely, at the natural ligand Gro-alpha. We then aim to show that the site of action is either intracellular or extracellular. Defining the mechanism of inhibition in Phase I will establish the feasibility of proceeding to Phase II, where we aim to precisely identify the site of action at the molecular level, define and optimize their pharmaceutics, and establish efficacy in an animal model of bronchopulmonary dysplasia. The market for these therapeutic compounds is estimated to be $50 million annually in the U.S.