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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
3R44HL072614-04S1
Application #
8056184
Study Section
Special Emphasis Panel (ZRG1-RES-F (10))
Program Officer
Blaisdell, Carol J
Project Start
2003-01-17
Project End
2010-06-30
Budget Start
2007-08-15
Budget End
2010-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$218,812
Indirect Cost
Name
Syntrix Biosystems, Inc.
Department
Type
DUNS #
114845659
City
Auburn
State
WA
Country
United States
Zip Code
98001
Lu, Xin; Horner, James W; Paul, Erin et al. (2017) Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature 543:728-732
Maeda, Dean Y; Peck, Angela M; Schuler, Aaron D et al. (2015) Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model. Bioorg Med Chem Lett 25:2280-4
Schuler, Aaron D; Engles, Courtney A; Maeda, Dean Y et al. (2015) Boronic acid-containing aminopyridine- and aminopyrimidinecarboxamide CXCR1/2 antagonists: Optimization of aqueous solubility and oral bioavailability. Bioorg Med Chem Lett 25:3793-7
Maeda, Dean Y; Peck, Angela M; Schuler, Aaron D et al. (2014) Discovery of 2-[5-(4-Fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic Acid (SX-517): Noncompetitive Boronic Acid Antagonist of CXCR1 and CXCR2. J Med Chem 57:8378-97
Maeda, Dean Y; Quinn, Mark T; Schepetkin, Igor A et al. (2010) Nicotinamide glycolates antagonize CXCR2 activity through an intracellular mechanism. J Pharmacol Exp Ther 332:145-52
Kallapur, Suhas G; Moss, Timothy J M; Auten Jr, Richard L et al. (2009) IL-8 signaling does not mediate intra-amniotic LPS-induced inflammation and maturation in preterm fetal lamb lung. Am J Physiol Lung Cell Mol Physiol 297:L512-9