| Description: |
SCH-527123 is a potent antagonist of both CXCR1 and CXCR2 with IC50 of 42 nM and 3 nM, respectively.
in vitro: Sch527123 inhibits chemokine binding to CXCR1 and CXCR2 receptors in an insurmountable manner and is categorized as an allosteric antagonist. Sch527123 inhibits neutrophil chemotaxis and myeloperoxidase release in response to CXCL1 and CXCL8 but has no effect on the response of these cells to C5a or formyl-methionyl-leucyl-phenylalanine. Sch527123 binding to CXCR1 and CXCR2 is both saturable and reversible. Sch527123 binds to CXCR1 with good affinity (Kd = 3.9 nM), the compound is CXCR2-selective (Kd = 0.049 nM). Sch527123 bound with high affinity to the CXCR2 receptors of mouse (Kd = 0.20 nM), rat (Kd = 0.20 nM), and cynomolgus monkey (Kd = 0.08 nM) and is a potent antagonist of CXCR2-mediated chemotaxis (IC50 ~3–6 nM). In contrast, Sch527123 bound to cynomolgus CXCR1 with lesser affinity (Kd = 41 nM) and weakly inhibited cynomolgus CXCR1-mediated chemotaxis (IC50 ~1000 nM).
in vivo: Oral treatment with Sch527123 blocks pulmonary neutrophilia (ED50 = 1.2 mg/kg) and goblet cell hyperplasia (32–38% inhibition at 1–3 mg/kg) in mice following the intranasal lipopolysaccharide (LPS) administration. In rats, Sch527123 suppresses the pulmonary neutrophilia (ED50 = 1.8 mg/kg) and increase in bronchoalveolar lavage (BAL) mucin content (ED50 =<0.1 mg/kg) induced by intratracheal (i.t.) LPS. Sch527123 also suppresses the pulmonary neutrophilia (ED50 = 1.3 mg/kg), goblet cell hyperplasia (ED50 = 0.7 mg/kg), and increase in BAL mucin content (ED50 = <1 mg/kg) in rats after i.t. administration of vanadium pentoxide. In cynomolgus monkeys, Sch527123 reduces the pulmonary neutrophilia induced by repeat bronchoscopy and lavage (ED50 = 0.3 mg/kg). |
