Synthesis and structure-activity relationships of oxamyl dipeptide caspase inhibitors developed for the treatment of liver disease

Hirokazu Ueno; Makoto Kawai; Hirohisa Shimokawa; Masako Hirota; Masashi Ohmi; Rie Sudo; Atsuko Ohta; Yoshimasa Arano; Kazunari Hattori; Takashi Ohmi; Naoto Kato; Midori Kojima; Yoshinobu Ueno; Mitsuko Yamamoto; Yukiko Moriguchi; Hiroyuki Eda; Kazunao Masubuchi

doi:10.1016/j.bmcl.2008.10.117

Synthesis and structure-activity relationships of oxamyl dipeptide caspase inhibitors developed for the treatment of liver disease

Bioorg Med Chem Lett. 2009 Jan 1;19(1):199-202. doi: 10.1016/j.bmcl.2008.10.117. Epub 2008 Nov 5.

Authors

Hirokazu Ueno¹, Makoto Kawai, Hirohisa Shimokawa, Masako Hirota, Masashi Ohmi, Rie Sudo, Atsuko Ohta, Yoshimasa Arano, Kazunari Hattori, Takashi Ohmi, Naoto Kato, Midori Kojima, Yoshinobu Ueno, Mitsuko Yamamoto, Yukiko Moriguchi, Hiroyuki Eda, Kazunao Masubuchi

Affiliation

¹ Discovery Chemistry Research, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Japan Inc, Aichi, Japan. Hirokazu.ueno@pfizer.com

PMID: 19013793
DOI: 10.1016/j.bmcl.2008.10.117

Abstract

The P4 region of a series of oxamyl dipeptide caspase inhibitors was optimized by the combination of anti-apoptotic activity in the Jurkat/Fas (JFas) cellular assay and membrane permeability in the PAMPA assay. Two highly potent anti-apoptotic agents with moderate membrane permeability, 29 and 36, showed strong in vivo efficacy in a murine model of alpha-Fas-induced liver injury.

MeSH terms

Animals
Apoptosis / drug effects
Caspase Inhibitors*
Cell Membrane Permeability / drug effects
Cysteine Proteinase Inhibitors / chemical synthesis*
Cysteine Proteinase Inhibitors / pharmacology
Humans
Jurkat Cells
Liver Diseases / drug therapy*
Mice
Structure-Activity Relationship
fas Receptor

Substances

Caspase Inhibitors
Cysteine Proteinase Inhibitors
fas Receptor