title: Inhibitors of human mitotic kinesin Eg5: characterization of the 4-phenyl-tetrahydroisoquinoline lead series.
abstract: 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).
authors.affiliation: Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, NJ 08543, USA. christine.tarby@bms.com
authors.forename: Christine M
authors.initials: CM
authors.lastname: Tarby
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kaltenbach
authors.forename: Tram
authors.initials: T
authors.lastname: Huynh
authors.forename: Andrew
authors.initials: A
authors.lastname: Pudzianowski
authors.forename: Henry
authors.initials: H
authors.lastname: Shen
authors.forename: Marie
authors.initials: M
authors.lastname: Ortega-Nanos
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.forename: John A
authors.initials: JA
authors.lastname: Newitt
authors.forename: Patricia A
authors.initials: PA
authors.lastname: McDonnell
authors.forename: Neil
authors.initials: N
authors.lastname: Burford
authors.forename: Craig R
authors.initials: CR
authors.lastname: Fairchild
authors.forename: Wayne
authors.initials: W
authors.lastname: Vaccaro
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
authors.forename: Joseph
authors.initials: J
authors.lastname: Naglich
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardis
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Roussell
mesh_terms: 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
chemical_list: 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