AMG 487 prevents the chemokines I-IP-10 and I-ITAC from binding to CXCR3. In the cellular assays, AMG 487 inhibits CXCR3-mediated cell migration with IC50 values of 8nM, 15nM and 36nM for I-IP-10, I-ITAC and MIG, respectively.
In vivo, AMG 487 (0.03-10 mg/kg, s.c.) exhibits significant reduction in cellular infiltration into the lungs in a dose dependent manner. AMG487 (5 mg/kg, s.c., twice daily) develops fewer metastases than that in vehicle-treated 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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
|Solubility||DMSO: ≥ 30 mg/mL|
Sequential metabolism of AMG 487, a novel CXCR3 antagonist, results in formation of quinone reactive metabolites that covalently modify CYP3A4 Cys239 and cause time-dependent inhibition of the enzyme.
Henne KR, et al. Drug Metab Dispos. 2012 Jul;40(7):1429-40. PMID: 22517972.
Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism.
Cambien B, et al. Br J Cancer. 2009 Jun 2;100(11):1755-64. PMID: 19436305.
Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer.
Walser TC, et al. Cancer Res. 2006 Aug 1;66(15):7701-7. PMID: 16885372.
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