Bronchopulmonary dysplasia (BPD) is a disease affecting infants who become oxygen dependent as a result of prolonged mechanical ventilation with supplemental oxygen early in life. Barotrauma and elevated levels of oxygen induce direct injury to the immature lung tissue, resulting in an inflammatory response and infiltration by circulating neutrophils. When neutrophils chemotax to the site of lung injury, the damage to the lung is compounded by the potent oxidant properties the neutrophils possess. Increased injury to the lung results in decreased blood oxygenation, requiring ventilation with progressively higher concentrations of oxygen that further accelerates the pace of injury. One way to break this vicious cycle of inflammation and injury is to block the recruitment of neutrophils to the lung. Novel inhibitors of neutrophil chemotaxis have been discovered that potently inhibit neutrophil chemotaxis both in vitro and in vivo. The goals of this SBIR Phase II proposal are to optimize the chemical structure of these chemotaxis inhibitors for potency, metabolic stability and intestinal absorption, and obtain the pharmacokinetic and toxicological data necessary for submission of an investigational new drug (IND) application for advancing these novel inhibitors towards clinical evaluation in humans.
