RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase.

Tumor necrosis factor-alpha (TNF-alpha), a cytokine secreted by activated monocytes/macrophages and T lymphocytes, has been implicated in several disease states, including rheumatoid arthritis, inflammatory bowel disease, septic shock, and osteoporosis. Monocyte/macrophage production of TNF-alpha is dependent on the mitogen-activated protein kinase p38. RWJ 67657 (4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol -2-yl]-3-butyn-1-ol) inhibited the release of TNF-alpha by lipopolysaccharide (a monocyte stimulus)-treated human peripheral blood mononuclear cells with an IC(50) of 3 nM, as well as the release of TNF-alpha from peripheral blood mononuclear cells treated with the superantigen staphylococcal enterotoxin B (a T cell stimulus), with an IC(50) value of 13 nM.

Identification of sites of degradation in a therapeutic monoclonal antibody by peptide mapping.

A peptide mapping procedure was developed to locate regions of a monoclonal antibody, OKT3, that undergo chemical modification as the molecule degrades upon storage. The structures of these peptide degradation products were investigated. Deamidation at specific asparagine residues and oxidation of a cysteine and several methionines were found to be major routes of OKT3 degradation.