title: Synthesis and structure-activity relationships of oxamyl dipeptide caspase inhibitors developed for the treatment of liver disease.
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.
authors.affiliation: Discovery Chemistry Research, Pfizer Global Research and Development, Nagoya Laboratories, Pfizer Japan Inc, Aichi, Japan. Hirokazu.ueno@pfizer.com
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ueno
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawai
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Masako
authors.initials: M
authors.lastname: Hirota
authors.forename: Masashi
authors.initials: M
authors.lastname: Ohmi
authors.forename: Rie
authors.initials: R
authors.lastname: Sudo
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ohta
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Arano
authors.forename: Kazunari
authors.initials: K
authors.lastname: Hattori
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohmi
authors.forename: Naoto
authors.initials: N
authors.lastname: Kato
authors.forename: Midori
authors.initials: M
authors.lastname: Kojima
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ueno
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Moriguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Eda
authors.forename: Kazunao
authors.initials: K
authors.lastname: Masubuchi
mesh_terms: 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
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D019014:fas Receptor