Inhibitors of human mitotic kinesin Eg5: characterization of the 4-phenyl-tetrahydroisoquinoline lead series.
In a high-throughput screening effort, a series of tetrahydroisoquinolines was identified as modest inhibitors of human Eg5. A medicinal chemistry optimization effort led to the identification of R-4-(3-hydroxyphenyl)-N,N-7,8-tetramethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (32a) as a potent inhibitor of human Eg5 (ATPase IC50 104 nM) with good anti-proliferative activity in A2780 cells (IC50 234 nM).
Tarby
Christine M
CM
Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, NJ 08543, USA. christine.tarby@bms.com
Kaltenbach
Robert F
RF
Huynh
Tram
T
Pudzianowski
Andrew
A
Shen
Henry
H
Ortega-Nanos
Marie
M
Sheriff
Steven
S
Newitt
John A
JA
McDonnell
Patricia A
PA
Burford
Neil
N
Fairchild
Craig R
CR
Vaccaro
Wayne
W
Chen
Zhong
Z
Borzilleri
Robert M
RM
Naglich
Joseph
J
Lombardo
Louis J
LJ
Gottardis
Marco
M
Trainor
George L
GL
Roussell
Deborah L
DL
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007546:Isoquinolines; C510705:N-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; D044005:Tetrahydroisoquinolines; D000251:Adenosine Triphosphatases; D016547:Kinesins