3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3.
Cysteine-dependant aspartyl protease (caspase) activation has been implicated as a part of the signal transduction pathway leading to apoptosis. It has been postulated that caspase-3 inhibition could attenuate cell damage after an ischemic event and thereby providing for a novel neuroprotective treatment for stroke. As part of a program to develop a small molecule inhibitor of caspase-3, a novel series of 3,4-dihydropyrimido(1,2-a)indol-10(2H)-ones (pyrimidoindolones) was identified. The synthesis, biological evaluation and structure-activity relationships of the pyrimidoindolones are described.
Havran
Lisa M
LM
Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. havranl@wyeth.com
Chong
Dan C
DC
Childers
Wayne E
WE
Dollings
Paul J
PJ
Dietrich
Arlene
A
Harrison
Boyd L
BL
Marathias
Vasilios
V
Tawa
Gregory
G
Aulabaugh
Ann
A
Cowling
Rebecca
R
Kapoor
Bhupesh
B
Xu
Weixin
W
Mosyak
Lidia
L
Moy
Franklin
F
Hum
Wah-Tung
WT
Wood
Andrew
A
Robichaud
Albert J
AJ
D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D004926:Escherichia coli; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020521:Stroke / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship
D061945:Caspase Inhibitors; D011480:Protease Inhibitors; D011744:Pyrimidinones; D053148:Caspase 3