title: 3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3.
abstract: 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.
authors.affiliation: Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. havranl@wyeth.com
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Havran
authors.forename: Dan C
authors.initials: DC
authors.lastname: Chong
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Childers
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dollings
authors.forename: Arlene
authors.initials: A
authors.lastname: Dietrich
authors.forename: Boyd L
authors.initials: BL
authors.lastname: Harrison
authors.forename: Vasilios
authors.initials: V
authors.lastname: Marathias
authors.forename: Gregory
authors.initials: G
authors.lastname: Tawa
authors.forename: Ann
authors.initials: A
authors.lastname: Aulabaugh
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cowling
authors.forename: Bhupesh
authors.initials: B
authors.lastname: Kapoor
authors.forename: Weixin
authors.initials: W
authors.lastname: Xu
authors.forename: Lidia
authors.initials: L
authors.lastname: Mosyak
authors.forename: Franklin
authors.initials: F
authors.lastname: Moy
authors.forename: Wah-Tung
authors.initials: WT
authors.lastname: Hum
authors.forename: Andrew
authors.initials: A
authors.lastname: Wood
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
mesh_terms: 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
chemical_list: D061945:Caspase Inhibitors; D011480:Protease Inhibitors; D011744:Pyrimidinones; D053148:Caspase 3