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

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...

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Veröffentlicht in:	Journal of medicinal chemistry 2005-11, Vol.48 (22), p.6779-6782
Hauptverfasser:	Linton, Steven D, Aja, Teresa, Armstrong, Robert A, Bai, Xu, Chen, Long-Shiuh, Chen, Ning, Ching, Brett, Contreras, Patricia, Diaz, Jose-Luis, Fisher, Craig D, Fritz, Lawrence C, Gladstone, Patricia, Groessl, Todd, Gu, Xin, Herrmann, Julia, Hirakawa, Brad P, Hoglen, Niel C, Jahangiri, Kathy G, Kalish, Vincent J, Karanewsky, Donald S, Kodandapani, Lalitha, Krebs, Joseph, McQuiston, Jeff, Meduna, Steven P, Nalley, Kip, Robinson, Edward D, Sayers, Robert O, Sebring, Kristen, Spada, Alfred P, Ternansky, Robert J, Tomaselli, Kevin J, Ullman, Brett R, Valentino, Karen L, Weeks, Suzanne, Winn, David, Wu, Joe C, Yeo, Pauline, Zhang, Cheng-zhi
Format:	Artikel
Sprache:	eng
Schlagworte:	Adult Alanine Transaminase - blood Animals Apoptosis - drug effects Aspartate Aminotransferases - blood Biological and medical sciences Biological Availability Caspase 3 Caspase Inhibitors Cholestasis - drug therapy Cholestasis - pathology Clinical Trials, Phase I as Topic Digestive system Half-Life Hepatitis C, Chronic - drug therapy Hepatocytes - drug effects Hepatocytes - pathology Humans Jurkat Cells Liver - drug effects Liver - pathology Liver Diseases - drug therapy Liver Diseases - enzymology Liver Diseases - etiology Medical sciences Mice Pentanoic Acids - chemical synthesis Pentanoic Acids - chemistry Pentanoic Acids - pharmacology Pharmacology. Drug treatments Rats Structure-Activity Relationship
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Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm050307e