W-54011

W-54011 is a potent and orally active non-peptide C5a receptor antagonist. W-54011 inhibits the binding of ¹²⁵I-labeled C5a to human neutrophils with a K_i value of 2.2 nM. W-54011 also inhibits C5a-induced intracellular Ca²⁺ mobilization, chemotaxis, and generation of ROS in human neutrophils with IC₅₀s of 3.1 nM, 2.7 nM, and 1.6 nM, respectively^[1]. IC50 & Target: Ki: 2.2 nM (C5a)sup>[1]
IC50: 3.1 nM (Ca²⁺ mobilization,), 2.7 nM (Chemotaxis), and 1.6 nM (ROS)^[1] In Vitro: In C5a-induced intracellular Ca²⁺ mobilization assay with human neutrophils, W-54011 does not show agonistic activity at up to 10 μM and shifts rightward the concentration-response curves to C5a without depressing the maximal responses, indicating that W-54011 is a full antagonist. At concentrations up to 10 μM, W-54011 does not affect Ca2+ mobilization stimulated with sub-maximally effective concentrations of fMLP (1 nM), plateletactivating factor (0.3 nM), and IL-8 (0.1 nM). This result demonstrates that W-54011 is highly specific for C5a receptor^[1]. In Vivo: W-54011 (3-30 mg/kg; oral administration; for 4 hours; male mongolian gerbils) treatment inhibited C5a-induced neutropenia in a dose-dependent manner in gerbils^[1].
The species selectivity of W-54011 is examined in rhC5a-induced intracellular Ca²⁺ mobilization of neutrophils in various species. The W-54011 is able to inhibit the response in cynomolgus monkeys and gerbils with IC₅₀ values of 1.7 nM and 3.2 nM, respectively, but not in mice, rats, guinea pigs, rabbits, and dogs^[1].