LY3000328 is a potent cathepsin S inhibitor (IC50 = 7.7 nM for the human enzyme). It is selective for cathepsin S over cathepsin L, K, B, and V (IC50s = >10,000, >10,000, 4,390, and 21,500 nM, respectively). LY3000328 (1-30 mg/kg) reduces aortic diameter in a mouse model of calcium chloride-induced abdominal aortic aneurysm.
LY 3000328 is a cathepsin S inhibitor for treatment of abdominal aortic aneurysm. Further provides methods for treating plaque instability, atherosclerosis, or autoimmune disorders such as rheumatoid arthritis, psoriasis, and lupus comprising administering a therapeutically effective amount of a disclosed compound.
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].
[1] wiener jj, sun s, thurmond rl. recent advances in the design of cathepsin s inhibitors. curr top med chem. 2010;10(7):717-32.
[2] lee-dutra a, wiener dk, sun s. cathepsin s inhibitors: 2004-2010. expert opin ther pat. 2011;21(3):311-37.
