W 54011

W-54011 is a potent, specific, and orally active CD88 (C5a receptor) antagonist. W-54011 inhibits the binding of 125I-labeled C5a to human neutrophils with a Ki value of 2.2 nM.IC50 value: 2.2 nM (Ki)Target: CD88 (C5a receptor)in vitro: W-54011 also inhibits C5a-induced intracellular Ca2+ mobilization, chemotaxis, and generation of reactive super oxide species in human neutrophils with IC50 alues of 3.1, 2.7, and 1.6 nM, respectively. In C5a-induced intracellular Ca2+ obilization 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. in vivo: Examination on the species specificity of W-54011 reveals 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) inhibits 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.

Signaling Pathways >> Immunology/Inflammation >> Complement System

Research Areas >> Inflammation/Immunology

Ki: 2.2 nM (C5a)sup>[1] IC50: 3.1 nM (Ca2+ mobilization,), 2.7 nM (Chemotaxis), and 1.6 nM (ROS)[1]

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].

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]. Animal Model: Male mongolian gerbils (6-12 weeks) injected with rhC5a[1] Dosage: 3 mg/kg, 10 mg/kg, 30 mg/kg Administration: Oral administration; for 4 hours Result: Inhibited C5a-induced neutropenia in a dose-dependent manner.

[1]. Sumichika H, et al. Identification of a potent and orally active non-peptide C5a receptor antagonist. J Biol Chem. 2002 Dec 20;277(51):49403-49407.