SCH527123 is a potent and selective antagonist of the human CXCR1 and CXCR2 receptors with IC50 of 42 nM and 3 nM, respectively. SCH-527123 bound with high affinity to the CXCR2 receptors of mouse (K(d) = 0.20 nM), rat (K(d) = 0.20 nM), and cynomolgus monkey (K(d) = 0.08 nM) and was a potent antagonist of CXCR2-mediated chemotaxis (IC(50) approximately 3-6 nM). In contrast, SCH527123 bound to cynomolgus CXCR1 with lesser affinity (K(d) = 41 nM) and weakly inhibited cynomolgus CXCR1-mediated chemotaxis (IC(50) approximately 1000 nM). Oral treatment with SCH527123 blocked pulmonary neutrophilia (ED(50) = 1.2 mg/kg) and goblet cell hyperplasia (32-38% inhibition at 1-3 mg/kg) in mice following the intranasal lipopolysaccharide (LPS) administration. SCH-527123 also suppressed the pulmonary neutrophilia (ED(50) = 1.3 mg/kg), goblet cell hyperplasia (ED(50) = 0.7 mg/kg), and increase in BAL mucin content (ED(50) = <1 mg/kg) in rats after i.t. administration of vanadium pentoxide. In vivo, SCH-527123 treatment decreased tumor growth and microvessel density when compared with vehicle-treated tumors.
|Source||The University of Birmingham (2015).SCH527123, Figure 5.5. (AbMole Bioscience, Kowloon, Hong Kong)|
|Cell Lines||CXCR2 and CXCR1|
|Concentrations||3nM (specific to CXCR2) and 42nM (required for concurrent CXCR1 inhibition).|
|Results||Pre-incubation with the dual CXCR1/2 inhibitor (SCH527123) at both concentrations (3 nM and 42 nM) caused a significant reduction in chemokinesis in gradients of both IL-8 and GROα, but only 3 nM caused a significant reduction of chemokinesis in Sol (Figure 5.5).|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial.
Nair P, et al. Clin Exp Allergy. 2012 Jul;42(7):1097-103. PMID: 22702508.
The CXCR2 antagonist, SCH-527123, shows antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models.
Ning Y, et al. Mol Cancer Ther. 2012 Jun;11(6):1353-64. PMID: 22391039.
A novel, orally active CXCR1/2 receptor antagonist, Sch527123, inhibits neutrophil recruitment, mucus production, and goblet cell hyperplasia in animal models of pulmonary inflammation.
Chapman RW, et al. J Pharmacol Exp Ther. 2007 Aug;322(2):486-93. PMID: 17496165.
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