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

P4 derivatives of the oxamyl dipeptide caspase inhibitors are reported. Compounds 29 and 36 exhibited moderate membrane permeability and potent in vivo efficacy in an α-Fas-induced liver injury model. The P4 region of a series of oxamyl dipeptide caspase inhibitors was optimized by the combination o...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009, Vol.19 (1), p.199-202
Hauptverfasser:	Ueno, Hirokazu, Kawai, Makoto, Shimokawa, Hirohisa, Hirota, Masako, Ohmi, Masashi, Sudo, Rie, Ohta, Atsuko, Arano, Yoshimasa, Hattori, Kazunari, Ohmi, Takashi, Kato, Naoto, Kojima, Midori, Ueno, Yoshinobu, Yamamoto, Mitsuko, Moriguchi, Yukiko, Eda, Hiroyuki, Masubuchi, Kazunao
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Apoptosis Apoptosis - drug effects Biological and medical sciences Caspase Caspase Inhibitors Cell Membrane Permeability - drug effects Cysteine Proteinase Inhibitors - chemical synthesis Cysteine Proteinase Inhibitors - pharmacology Digestive system fas Receptor Humans Jurkat Jurkat Cells Liver Liver Diseases - drug therapy Medical sciences Mice Oxamyl dipeptide PAMPA Permeability Pharmacology. Drug treatments Structure-Activity Relationship α-Fas
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Zusammenfassung:	P4 derivatives of the oxamyl dipeptide caspase inhibitors are reported. Compounds 29 and 36 exhibited moderate membrane permeability and potent in vivo efficacy in an α-Fas-induced liver injury model. 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 α-Fas-induced liver injury.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2008.10.117