Avacopan (CCX168) blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. Avacopan competitively and selectively blocked C5a-induced calcium mobilization in purified human neutrophils, with an IC50 value of 0.2 nM.
In vivo, in mice dosed orally with 0.03 mg/kg of CCX168, the resulting plasma CCX168 concentration of 15 nM (8.7 ng/mL) reduces the drop in circulating leukocytes from 53% to 25%. In mice administered 0.3 mg/kg of CCX168, the resulting plasma CCX168 concentration of 75 nM (44 ng/mL) reduces the drop in circulating leukocytes from 53% to only 10% relative to baseline (p<0.05 for CCX168 vs. vehicle control). Oral doses of CCX168 of either 3 or 30 mg/kg completely blocks C5a-induced leukopenia in hC5aR knock-in mice.
|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.
|Solubility||DMSO: ≥ 9 mg/mL|
Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.
Bekker P, et al. PLoS One. 2016 Oct 21;11(10):e0164646. PMID: 27768695.
C5a receptor (CD88) blockade protects against MPO-ANCA GN.
Xiao H, et al. J Am Soc Nephrol. 2014 Feb;25(2):225-31. PMID: 24179165.
JNJ-47117096 is potent and selective MELK inhibitor with IC50 of 23 nM.
Phytohemagglutinin is a lectin obtained from the red kidney bean that binds to the membranes of T-cells, stimulates metabolic activity and involves inflammatory pathways.
Apilimod is a potent IL-12/IL-23 inhibitor, and it is also a cell permeable small molecule which specifically inhibits PIKfyve with an IC50 of 14 nM in an in vitro kinase assay.
10-Hydroxy-trans-2-decenoic acid is the principal lipid component in royal jelly which is the food for queen and larvae honeybees.
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