LY 3000328

LY 3000328 (Z-FL-COCHO) is a potent and selective Cathepsin S (Cat S) inhibitor with IC₅₀s of 7.7 and 1.67 nM for hCat S and mCat S, respectively. IC50 & Target:IC50: 7.7±5.85 nM (hCat S), 1.67±1.17 (mCat S)^[1] In Vitro:LY 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 [³H]-astemizole in an assay with HEK293 membrane preparation, indicating low potential of hERG blockade^[1]. 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^[2]. In Vivo:The efficacies of LY 3000328 is studied in a mouse model of abdominal aortic aneurysm (AAA). In this model, inflammation is induced using CaCl₂ 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^[1].