Syuji Ehara

Identification of a Potent and Orally Active Non-peptide C5a Receptor Antagonist

The anaphylatoxin C5a is a potent chemotactic factor for neutrophils and other leukocytes, and functions as an important inflammatory mediator. Through a high capacity screening followed by chemical optimization, we identified a novel non-peptide C5a receptor antagonist,N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1- carboxamide hydrochloride (W-54011). W-54011 inhibited the binding of125I-labeled C5a to human neutrophils with aK i value of 2.2 nm. W-54011 also inhibited C5a-induced intracellular Ca2+ mobilization, chemotaxis, and generation of reactive super oxide species in human neutrophils with IC50 values of 3.1, 2.7, and 1.6 nm, respectively. In C5a-induced intracellular Ca2+ mobilization assay with human neutrophils, W-54011 did not show agonistic activity at up to 10 μm and shifted rightward the concentration-response curves to C5a without depressing the maximal responses. Examination on the species specificity of W-54011 revealed that it was able to inhibit C5a-induced intracellular Ca2+ mobilization in neutrophils of cynomolgus monkeys and gerbils but not mice, rats, guinea pigs, rabbits, and dogs. In gerbils, oral administration of W-54011 (3–30 mg/kg) inhibited C5a-induced neutropenia in a dose-dependent manner. The present report is the first description of an orally active non-peptide C5a receptor antagonist that could contribute to the treatment of inflammatory diseases mediated by C5a.