Kinesin spindle protein (KSP) inhibitors. Part 7: Design and synthesis of 3,3-disubstituted dihydropyrazolobenzoxazines as potent inhibitors of the mitotic kinesin KSP.
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.
Garbaccio
Robert M
RM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_garbaccio@merck.com
Tasber
Edward S
ES
Neilson
Lou Anne
LA
Coleman
Paul J
PJ
Fraley
Mark E
ME
Olson
Christy
C
Bergman
Jeff
J
Torrent
Maricel
M
Buser
Carolyn A
CA
Rickert
Keith
K
Walsh
Eileen S
ES
Hamilton
Kelly
K
Lobell
Robert B
RB
Tao
Weikang
W
South
Vicki J
VJ
Diehl
Ronald E
RE
Davide
Joseph P
JP
Yan
Youwei
Y
Kuo
Lawrence C
LC
Li
Chunze
C
Prueksaritanont
Thomayant
T
Fernandez-Metzler
Carmen
C
Mahan
Elizabeth A
EA
Slaughter
Donald E
DE
Salata
Joseph J
JJ
Kohl
Nancy E
NE
Huber
Hans E
HE
Hartman
George D
GD
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