Document Report Card

ID: ALA1141033

Journal: J Med Chem

Title: First-in-class pan caspase inhibitor developed for the treatment of liver disease.

Authors: Linton SD, Aja T, Armstrong RA, Bai X, Chen LS, Chen N, Ching B, Contreras P, Diaz JL, Fisher CD, Fritz LC, Gladstone P, Groessl T, Gu X, Herrmann J, Hirakawa BP, Hoglen NC, Jahangiri KG, Kalish VJ, Karanewsky DS, Kodandapani L, Krebs J, McQuiston J, Meduna SP, Nalley K, Robinson ED, Sayers RO, Sebring K, Spada AP, Ternansky RJ, Tomaselli KJ, Ullman BR, Valentino KL, Weeks S, Winn D, Wu JC, Yeo P, Zhang CZ.

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.

CiteXplore: 16250635

DOI: 10.1021/jm050307e