Author/Authors :
Darin J. Gustin، نويسنده , , Clark A. Sehon، نويسنده , , Jianmei Wei، نويسنده , , Hui Cai، نويسنده , , Steven P. Meduna، نويسنده , , Haripada Khatuya، نويسنده , , Siquan Sun، نويسنده , , Yin Gu، نويسنده , , Wen Jiang، نويسنده , , Robin L. Thurmond، نويسنده , , Lars Karlsson، نويسنده , , James P. Edwards، نويسنده ,
Abstract :
A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
