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 of (125)I-labeled C5a to human neutrophils with a K(i) value of 2.2 nm. W-54011 also inhibited C5a-induced intracellular Ca(2+) mobilization, chemotaxis, and generation of reactive super oxide species in human neutrophils with IC(50) values of 3.1, 2.7, and 1.6 nm, respectively. In C5a-induced intracellular Ca(2+) mobilization assay with human neutrophils, W-54011 did not show agonistic activity at up to 10 microm 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 Ca(2+) 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.