1-(5-Chloro-2-alkoxyphenyl)-3-(5-cyano- pyrazi-2-yl)ureas as Potent and Selective Inhibitors of Chk1 Kinase:  Synthesis, Preliminary SAR, and Biological Activities

• Published in: Journal of medicinal chemistry 2005-05, Vol.48 (9), p.3118-3121
• Main Authors: Wang, Gary T, Li, Gaoquan, Mantei, Robert A, Chen, Zehan, Kovar, Peter, Gu, Wendy, Xiao, Zhan, Zhang, Haiying, Sham, Hing L, Sowin, Thomas, Rosenberg, Saul H, Lin, Nan-Horng
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Camptothecin - pharmacology; Cell Cycle - drug effects; Checkpoint Kinase 1; Crystallography, X-Ray; Doxorubicin - pharmacology; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Nitriles - chemical synthesis; Nitriles - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Pyrazoles - chemical synthesis; Pyrazoles - pharmacology; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm048989d

The discovery of 1-(5-chloro-2-alkoxyphenyl)-3-(5-cyanopyrazin-2-yl)ureas as a new class of potent (IC50 values of 3−10 nM) and selective inhibitors of Chk1 kinase was described. One of these compounds (2e) potentiates HeLa cells by over 22-fold against doxorubicin in an antiproliferation assay, and SW620 cells against camptothecin by 20-fold in an antiproliferation assay and 14-fold in a soft agar assay. Flow cytometry (FACS) analysis confirmed that 2e abrogated G2 checkpoint arrest of H1299 cells caused by doxorubicin and S checkpoint arrest caused by camptothecin.