Download MendeleySynthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors
Li, G., Hasvold, L.A., Tao, Z.-F., Wang, G.T., Gwaltney II, S.L., Patel, J., Kovar, P., Credo, R.B., Chen, Z., Zhang, H., Park, C., Sham, H.L., Sowin, T., Rosenberg, S.H., Lin, N.-H.(2006) Bioorg Med Chem Lett 16: 2293-2298
- PubMed: 16446090
- DOI: https://doi.org/10.1016/j.bmcl.2006.01.028
- Primary Citation of Related Structures:
2YWP - PubMed 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.
Organizational Affiliation:
Cancer Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. Gaoquan.Li@abbott.com
