Kinesin spindle protein (KSP) inhibitors. Part 3: synthesis and evaluation of phenolic 2,4-diaryl-2,5-dihydropyrroles with reduced hERG binding and employment of a phosphate prodrug strategy for aqueous solubility.
2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy.
Garbaccio
Robert M
RM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. robert_garbaccio@merck.com
Fraley
Mark E
ME
Tasber
Edward S
ES
Olson
Christy M
CM
Hoffman
William F
WF
Arrington
Kenneth L
KL
Torrent
Maricel
M
Buser
Carolyn A
CA
Walsh
Eileen S
ES
Hamilton
Kelly
K
Schaber
Michael D
MD
Fernandes
Christine
C
Lobell
Robert B
RB
Tao
Weikang
W
South
Vicki J
VJ
Yan
Youwei
Y
Kuo
Lawrence C
LC
Prueksaritanont
Thomayant
T
Slaughter
Donald E
DE
Shu
Cathy
C
Heimbrook
David C
DC
Kohl
Nancy E
NE
Huber
Hans E
HE
Hartman
George D
GD
D000818:Animals; D019540:Area Under Curve; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D016547:Kinesins / Q000037:antagonists & inhibitors*; D011355:Prodrugs; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D008941:Spindle Apparatus / Q000737:chemistry; D014867:Water
D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D011355:Prodrugs; D011758:Pyrroles; D014867:Water; D016547:Kinesins