Synthesis and structure-activity relationships of oxamyl dipeptide caspase inhibitors developed for the treatment of liver disease.
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.
Ueno
Hirokazu
H
Discovery Chemistry Research, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Japan Inc, Aichi, Japan. Hirokazu.ueno@pfizer.com
Kawai
Makoto
M
Shimokawa
Hirohisa
H
Hirota
Masako
M
Ohmi
Masashi
M
Sudo
Rie
R
Ohta
Atsuko
A
Arano
Yoshimasa
Y
Hattori
Kazunari
K
Ohmi
Takashi
T
Kato
Naoto
N
Kojima
Midori
M
Ueno
Yoshinobu
Y
Yamamoto
Mitsuko
M
Moriguchi
Yukiko
Y
Eda
Hiroyuki
H
Masubuchi
Kazunao
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D002463:Cell Membrane Permeability / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008107:Liver Diseases / Q000188:drug therapy*; D051379:Mice; D013329:Structure-Activity Relationship; D019014:fas Receptor
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D019014:fas Receptor