Kinesin spindle protein (KSP) inhibitors. Part 2: the design, synthesis, and characterization of 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP.
The evolution of 2,4-diaryl-2,5-dihydropyrroles as inhibitors of KSP is described. Introduction of basic amide and urea moieties to the dihydropyrrole nucleus enhanced potency and aqueous solubility, simultaneously, and provided compounds that caused mitotic arrest of A2780 human ovarian carcinoma cells with EC(50)s<10nM. Ancillary hERG activity was evaluated for this series of inhibitors.
Fraley
Mark E
ME
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. mark_fraley@merck.com
Garbaccio
Robert M
RM
Arrington
Kenneth L
KL
Hoffman
William F
WF
Tasber
Edward S
ES
Coleman
Paul J
PJ
Buser
Carolyn A
CA
Walsh
Eileen S
ES
Hamilton
Kelly
K
Fernandes
Christine
C
Schaber
Michael D
MD
Lobell
Robert B
RB
Tao
Weikang
W
South
Victoria J
VJ
Yan
Youwei
Y
Kuo
Lawrence C
LC
Prueksaritanont
Thomayant
T
Shu
Cathy
C
Torrent
Maricel
M
Heimbrook
David C
DC
Kohl
Nancy E
NE
Huber
Hans E
HE
Hartman
George D
GD
D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000473:pathology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000737:chemistry
D011758:Pyrroles; D016547:Kinesins