title: Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors.
abstract: Based on the X-ray crystallography of our lead compound 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint kinase 1 (Chk1) enzyme, we modified R4, and to a lesser extent, R2, and R5 of the phenyl ring, and made a variety of N-aryl-N'-pyrazinylurea Chk1 inhibitors. Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound 8i provided the best overall results in the cellular assays as it abrogated doxorubicin-induced cell cycle arrest (IC50=1.7 microM) and enhanced doxorubicin cytotoxicity (IC50=0.44 microM) while displaying no single agent activity.
authors.affiliation: Cancer Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. Gaoquan.Li@abbott.com
authors.forename: Gaoquan
authors.initials: G
authors.lastname: Li
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hasvold
authors.forename: Zhi-Fu
authors.initials: ZF
authors.lastname: Tao
authors.forename: Gary T
authors.initials: GT
authors.lastname: Wang
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Gwaltney
authors.forename: Jyoti
authors.initials: J
authors.lastname: Patel
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Robert B
authors.initials: RB
authors.lastname: Credo
authors.forename: Zehan
authors.initials: Z
authors.lastname: Chen
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Chang
authors.initials: C
authors.lastname: Park
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Thomas
authors.initials: T
authors.lastname: Sowin
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D004317:Doxorubicin; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1