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First-in-Class Pan Caspase Inhibitor Developed for the Treatment of Liver Disease

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journal contribution
posted on 03.11.2005, 00:00 by Steven D. Linton, Teresa Aja, Robert A. Armstrong, Xu Bai, Long-Shiuh Chen, Ning Chen, Brett Ching, Patricia Contreras, Jose-Luis Diaz, Craig D. Fisher, Lawrence C. Fritz, Patricia Gladstone, Todd Groessl, Xin Gu, Julia Herrmann, Brad P. Hirakawa, Niel C. Hoglen, Kathy G. Jahangiri, Vincent J. Kalish, Donald S. Karanewsky, Lalitha Kodandapani, Joseph Krebs, Jeff McQuiston, Steven P. Meduna, Kip Nalley, Edward D. Robinson, Robert O. Sayers, Kristen Sebring, Alfred P. Spada, Robert J. Ternansky, Kevin J. Tomaselli, Brett R. Ullman, Karen L. Valentino, Suzanne Weeks, David Winn, Joe C. Wu, Pauline Yeo, Cheng-zhi Zhang
A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure−activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of α-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.