Novel pyrazinone mono-amides as potent and reversible caspase-3 inhibitors.
The iterative process for the discovery of a series of pyrazinone mono-amides as potent, selective and reversible non-peptide caspase-3 inhibitors (e.g., M826 and M867) is reported. These compounds display potent anti apoptotic activities in a number of cell based systems in vitro as well as in several animal models in vivo.
Han
Yongxin
Y
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada & Co., PO Box 1005, Pointe-Claire-Dorval, Quebec, Canada H9R 4P8. yongxin_han@merck.com
Giroux
André
A
Colucci
John
J
Bayly
Christopher I
CI
Mckay
Daniel J
DJ
Roy
Sophie
S
Xanthoudakis
Steve
S
Vaillancourt
John
J
Rasper
Dita M
DM
Tam
John
J
Tawa
Paul
P
Nicholson
Donald W
DW
Zamboni
Robert J
RJ
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D061945:Caspase Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007962:Leukocytes / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects; D011719:Pyrazines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D011719:Pyrazines; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3