Kinesin spindle protein (KSP) inhibitors. Part 6: Design and synthesis of 3,5-diaryl-4,5-dihydropyrazole amides as potent inhibitors of the mitotic kinesin KSP.
3,5-diaryl-4,5-dihydropyrazoles were discovered to be potent KSP inhibitors with excellent in vivo potency. These enzyme inhibitors possess desirable physical properties that can be readily modified by incorporation of a weakly basic amine. Careful adjustment of amine basicity was essential for preserving cellular potency in a multidrug resistant cell line while maintaining good aqueous solubility.
Coleman
Paul J
PJ
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. paul_coleman@merck.com
Schreier
John D
JD
Cox
Christopher D
CD
Fraley
Mark E
ME
Garbaccio
Robert M
RM
Buser
Carolyn A
CA
Walsh
Eileen S
ES
Hamilton
Kelly
K
Lobell
Robert B
RB
Rickert
Keith
K
Tao
Weikang
W
Diehl
Ronald E
RE
South
Vicki J
VJ
Davide
Joseph P
JP
Kohl
Nancy E
NE
Yan
Youwei
Y
Kuo
Lawrence
L
Prueksaritanont
Thomayant
T
Li
Chunze
C
Mahan
Elizabeth A
EA
Fernandez-Metzler
Carmen
C
Salata
Joseph J
JJ
Hartman
George D
GD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D019450:Genes, MDR / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008938:Mitosis / Q000187:drug effects*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000577:Amides; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; C470243:KIF11 protein, human; D011720:Pyrazoles; D016547:Kinesins