XL-784 (C09-1185-349)

XL-784 is a selective matrix metalloproteinases (MMP) inhibitor, with IC 50 s of ~1900, 0.81, 120, 10.8, 18, 0.56 nM for MMP-1 ，MMP-2， MMP-3 ，MMP-8，MMP-9， MMP-13 ，respectively.In VitroXL-784 is a highly potent, low-molecular-weight (1,122 g/mol) inhibitor of MMPs that has very limited aqueous solubility (20 μg/mL). XL-784 potently inhibits MMP-2, MMP-13, and/nADAM10 [TNF-α-converting enzyme (TACE)] activity in vitro, with IC 50 values in the range of 1-2 nM. XL-784 also inhibits MMP-9 (IC 50 ~20 nM) activity and ADAM17 (IC 50 ~70 nM) also known as TACE. However, it exhibits low potency for inhibition of MMP-1 (IC 50 ~2,000 nM). MCE has not independently confirmed the accuracy of these methods. They are for reference only.In VivoAll mice tolerate the treatments similarly. Control mice all developed aneurysms with a mean %△AD of 158.5%±4.3%. Treatment with all doses of XL-784 and doxycycline are effective in inhibiting aortic dilatation. There is a clear dose-response relationship between XL-784 and reductions in aortic dilatation at harvest (50 mg/kg 140.4% ±3.2%; 125 mg/kg 129.3% ±5.1%; 250 mg/kg 119.2%±3.5%; all Ps <0.01 compared to control). This continues with the higher doses (375 mg/kg 88.6%±4.4%; 500 mg/kg 76.0%±3.5%). The highest 2 doses of XL-784 tested are more effective than doxycycline (112.2%±2.0%, P<0.05) in inhibiting maximal dilatation of the aorta after elastase perfusion. MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal administrationMice A total of 89 mice undergo aortic perfusion. Beginning the day of perfusion, animals are treated with the study drug (e.g., XL-784), a negative control, or doxycycline. 76 animals survive to sacrifice and are included in the analysis. Animals treated with the experimental agent, XL-784 , receive gavage daily with the agent diluted in 0.1 mL of Cremophor, a nonionic castor oil-based solubilizer and emulsifying agent. Three doses of the drug are used, 50 (n=17), 125 (n=17), and 250 mg/kg per d (n=18) administered as a single daily dose. The fifth group of mice do not receive a gavage treatment but are treated with doxycycline (n=19) in their drinking water at a concentration 100 mg/kg per d of the animals. In the second treatment protocol, a total of 50 animals underwent aortic perfusion and 47 animals survive for analysis at 14 days. The 5 treatment groups are XL-784 at 250, 375, or 500 mg/kg , Cremaphor diluent alone, or doxycycline 100 mg/kg. Animals are assigned in groups of 3 to a treatment group rotating randomly through each treatment group until there are 9 animals in each group except for the 500 mg/kg per d group which totaled to 14 animals . aladdin has not independently confirmed the accuracy of these methods. They are for reference only.Form:SolidIC50& Target:MMP-2 0.81 nM (IC 50 ) MMP13 0.56 nM (IC 50 ) MMP-8 10.8 nM (IC 50 ) MMP-9 18 nM (IC 50 ) MMP-3 120 nM (IC 50 ) MMP-1 1900 nM (IC 50 ). Specification: 0.98 Molecular Formula: C21H21ClF2N3O8S[-] Molecular Weight: 548.92 PubChem CID: 74439626 Isomeric SMILES: COCCOC(=O)N1CCN(C(C1)C(=O)NO)S(=O)(=O)C2=CC(=C(C(=C2)F)OC3=CC=C(C=C3)Cl)F