title: Kinesin spindle protein (KSP) inhibitors. Part 7: Design and synthesis of 3,3-disubstituted dihydropyrazolobenzoxazines as potent inhibitors of the mitotic kinesin KSP.
abstract: Observations from two structurally related series of KSP inhibitors led to the proposal and discovery of dihydropyrazolobenzoxazines that possess ideal properties for cancer drug development. The synthesis and characterization of this class of inhibitors along with relevant pharmacokinetic and in vivo data are presented. The synthesis is highlighted by a key [3+2] cycloaddition to form the pyrazolobenzoxazine core followed by diastereospecific installation of a quaternary center.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_garbaccio@merck.com
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.forename: Edward S
authors.initials: ES
authors.lastname: Tasber
authors.forename: Lou Anne
authors.initials: LA
authors.lastname: Neilson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Christy
authors.initials: C
authors.lastname: Olson
authors.forename: Jeff
authors.initials: J
authors.lastname: Bergman
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamilton
authors.forename: Robert B
authors.initials: RB
authors.lastname: Lobell
authors.forename: Weikang
authors.initials: W
authors.lastname: Tao
authors.forename: Vicki J
authors.initials: VJ
authors.lastname: South
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Diehl
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Davide
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: Chunze
authors.initials: C
authors.lastname: Li
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernandez-Metzler
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mahan
authors.forename: Donald E
authors.initials: DE
authors.lastname: Slaughter
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Salata
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D015195:Drug Design; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship