Description
Brivanib alaninate (BMS-582664) is the prodrug of BMS-540215, an ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM
Storage
2 years -20 centigrade Powder; 2 weeks 4 centigrade in DMSO; 6 months -80 centigrade in DMSO.
Targets
VEGFR2, Flk1, VEGFR1, FGFR1
IC50
25 nM; 89 nM; 380 nM; 148 nM
Molecular Formula
C22H24FN5O4
Chemical Name
(S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate
Solubility
DMSO 88 mg/mL; Water <1 mg/mL; Ethanol 88 mg/mL
In vitro
BMS-582664 inhibits VEGF-stimulated and FGF-stimulated proliferating of HUVECs with IC50 of 40 nM and 276 nM. BMS-582664 (2 μM) significantly inhibits VEGFR2, FGFR1, ERK1/2 and Akt phosphorylation in VEGF- and bFGF-stimulated SK-HEP1 cells and HepG-2 cells, while BMS-582664 alone has little effect on levels of phosphorylated ERK1/2, Akt, VEGFR2, and FGFR1 in nonstimulated cells.BMS-582664 inhibits CYP2C19, CYP3A4(BFC) and CYP3A4 (BzRes) with IC50 of 2.4 μM, 0.51 μM and 1.6 μM, respectively. BMS-582664 exhibits high solid state stability (only 0.3% degradation at 50℃ with desiccant over a period of 12 weeks) and acceptable solution state stability up to pH 6.5.
In vivo
BMS-582664 (50 mg/kg) results in AUC of 136 μM×hr and Cmax of 41 μM in mouse. BMS-582664 (60 mg/kg, orally) is rapidly absorbed with Tmax of 1 hour, a favorable half-life (t1/2) of 2.7 hours and mean residence time (MRT) of 3.6 hours in mouse. BMS-582664 (25 mg/kg) results in AUC of 13.4 μM×hr and Cmax of 6.4 μM in rat. BMS-582664 dose-dependently inhibits the growth of established tumors with tumor growth inhibition of 85% and 97% at dose of 60 mg/kg and 90 mg/kg in H3396 xenografts athymic mice. BMS-582664 inhibits the growth rate of tumors in mice with patient-derived xenograft line 06-0606 by 55% and 13% at dose of 50 mg/kg and 100 mg/kg. BMS-582664 (60 mg/kg, orally) significantly reduces tumor weight at sacrifice, increases apoptosis, reduces microvessel density, inhibits of cell proliferation, and down-regulates cell cycle regulators in mice with patient-derived xenograft line 06-0606.BMS-582664 dose-dependently inhibits the growth of established tumors with tumor growth inhibition of 85% and 97% at dose of 80 mg/kg and 107 mg/kg in a L2987 nonsmall cell lung tumor xenografts assay in athymic mice.BMS-582664 (100 mg/kg) significantly modulates tyrosine kinase receptor 1 (Tie-1), collagen type IV alpha1 (Col4a1), complement component 1, q subcomponent receptor 1 (C1qr1), angiotensin receptor-like 1 (Agtrl1), and vascular endothelial-cadherin (Cdh5) in L2987 nonsmall cell lung tumor xenografts assay in athymic mice. BMS-582664 (100 mg/kg) inhibits the new growth of endothelial cells in two xenografts mouse models, L2987 and HCT116.
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