Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Sumichika, H. et al.

Sumichika, Sakata, Sato, Takeshita, Ishibuchi, Nakamura, Kamahori, Ehara, Itoh, Ohtsuka, Ohbora, Mishina, Komatsu, Naka,

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 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.[1]

References

Identification of a potent and orally active non-peptide C5a receptor antagonist. Sumichika, H., Sakata, K., Sato, N., Takeshita, S., Ishibuchi, S., Nakamura, M., Kamahori, T., Ehara, S., Itoh, K., Ohtsuka, T., Ohbora, T., Mishina, T., Komatsu, H., Naka, Y. J. Biol. Chem. (2002) [Pubmed]

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