MEDI 247 |
| Asthma involves airway inflammation that includes the recruitment of neutrophils, eosinophils, and mast cells to sites of injury. Neutrophils are also important in chronic obstructive pulmonary disease (COPD), for which there is a large unmet medical need. Leukocyte serine proteases such as cathepsin G (Cat G) and chymase can degrade extracellular matrix and trigger the release of pro-inflammatory mediators. Neutrophil Cat G degrades matrix proteins, damages airway epithelial celIs, and stimulates vascular permeability; mast cell chymase plays an important role in the pathogenesis of asthma. With the aid of structure-based drug design, we discovered a nonpeptide, dual inhibitor of Cat G and chymase (JNJ-10311795) and a selective, nonpeptide chymase inhibitor, both possessing novel chemotypes. These compounds were advanced into preclinical development. JNJ-10311795 markedly reduced neutrophil counts in a rat peritonitis model (iv) and was efficacious in the sheep model of asthma (it). The chymase inhibitor was orally efficacious in a hamster model of cutaneous inflammation and the sheep asthma model. |
|
New Approaches for the Treatment of Pulmonary Inflammatory Diseases
8:30 AM-11:50 AM, Wednesday, August 22, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |