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

  • J Med Chem. 2005 Nov 3;48(22):6779-82. doi: 10.1021/jm050307e.
Steven D Linton  1 ,  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
Affiliations
  • 1. Idun Pharmaceuticals, 9380 Judicial Drive, San Diego, CA 92121, USA. [email protected]
PMID: 16250635 DOI: 10.1021/jm050307e
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.