Solid-phase analogue synthesis of caspase-3 inhibitors via palladium-catalyzed amination of 3-bromopyrazinones.
Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact on the treatment of several degenerative diseases. Here we report the synthesis of reversible inhibitors via a solid-support palladium-catalyzed amination of 3-bromopyrazinones and the discovery of a pan-caspase reversible inhibitor.
Isabel
Elise
E
Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., PO Box 1005, Pointe-Claire-Dorval, Quebec, Canada H9R 4P8. elise_isabel@merck.com
Aspiotis
Renee
R
Black
W Cameron
WC
Colucci
John
J
Fortin
Réjean
R
Giroux
André
A
Grimm
Erich L
EL
Han
Yongxin
Y
Mellon
Christophe
C
Nicholson
Donald W
DW
Rasper
Dita M
DM
Renaud
Johanne
J
Roy
Sophie
S
Tam
John
J
Tawa
Paul
P
Vaillancourt
John P
JP
Xanthoudakis
Steven
S
Zamboni
Robert J
RJ
D000586:Amination; D061945:Caspase Inhibitors; D002384:Catalysis; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D010165:Palladium / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
D061945:Caspase Inhibitors; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D011719:Pyrazines; D011994:Recombinant Proteins; D010165:Palladium