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, [......],
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
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ABSTRACT: 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 alpha-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.
Journal of Medicinal Chemistry 12/2005; 48(22):6779-82. · 5.25 Impact Factor
