LY 3000328 (C09-1142-643)

LY 3000328 (Z-FL-COCHO) is a potent and selective Cathepsin S (Cat S) inhibitor with IC 50 s of 7.7 and 1.67 nM for hCat S and mCat S, respectively.In VitroLY 3000328 maintains excellent in vitro potency and selectivity. LY 3000328 shows low in vitro CYP450 inhibition (<15% at 10 μM for CYP3A4, CYP2D6, and CYP2C9); low in vitro metabolism in mouse, rat, dog, and human liver microsomes (<20% after 30 min incubation at 4 μM); and good permeability (MDCK A-B>4%). At a 100 μM concentration of LY 3000328 there is only 6% displacement of [ 3 H]-astemizole in an assay with HEK293 membrane preparation, indicating low potential of hERG blockade. LY 3000328 is a potent and specific inhibitor of cathepsin S (CatS). Inhibition of CatS activity in plasma would be 50% of maximal when LY 3000328 plasma concentration is approximately 60 ng/mL. MCE has not independently confirmed the accuracy of these methods. They are for reference only.In VivoThe efficacies of LY 3000328 is studied in a mouse model of abdominal aortic aneurysm (AAA). In this model, inflammation is induced using CaCl 2 applied to the ablumenal surface. It is shown that features of the disease state in this model resemble those of human AAA. LY 3000328 exhibits a dose-responsive aortic diameter reduction at 1, 3, 10, and 30 mg/kg. At the lowest dose of 1 mg/kg of LY 3000328, the aortic diameter is reduced by 58%, then 83% at 3 mg/kg, and 87% at 10 mg/kg. The exposure (AUC) for both compounds increased in a dose-dependent manner, suggesting that the drug disposition properties of LY 3000328 are favorable . MCE has not independently confirmed the accuracy of these methods. They are for reference only.Form:SolidIC50& Target:cathepsin S. Specification: 0.98 Molecular Formula: C25H29FN4O5 Molecular Weight: 484.5 PubChem CID: 67475270 Isomeric SMILES: CNC(=O)O[C@H]1COC2=C([C@@H]1NC(=O)C3=CC=C(C=C3)F)C=C(C=C2)N4CCN(CC4)C5COC5