Macrocyclic Ureas as Potent and Selective Chk1 Inhibitors: An Improved Synthesis, Kinome Profiling, Structure-Activity Relationships, and Preliminary Pharmacokinetics

Bioorg Med Chem Lett. 2007 Dec 1;17(23):6593-601. doi: 10.1016/j.bmcl.2007.09.063. Epub 2007 Sep 22.

Abstract

A new series of potent macrocyclic urea-based Chk1 inhibitors are described. A detailed SAR study on the 4-position of the phenyl ring of the 14-member macrocyclic ureas 1a and d led to the identification of the potent Chk1 inhibitors 2, 5-7, 10, 13, 14, 19-21, 25, 27, and 31-34. These compounds significantly sensitize tumor cells to the DNA-damaging antitumor agent doxorubicin in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and camptothecin-induced S checkpoints, indicating that the potent biological activities of these compounds are mechanism-based through Chk1 inhibition. Kinome profiling analysis of a representative macrocyclic urea 25 against a panel of 120 kinases indicates that these novel macrocyclic ureas are highly selective Chk1 inhibitors. Preliminary PK studies of 1a and b suggest that the 14-member macrocyclic inhibitors may possess better PK properties than their 15-member counterparts. An improved synthesis of 2 and 20 by using 2-(trimethylsilyl)ethoxycarbonyl (Teoc) to protect the amino group not only readily provided the desired compounds in pure form but also facilitated the scale up of potent compounds for various biological studies.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Catalysis
  • Checkpoint Kinase 1
  • HeLa Cells
  • Humans
  • Macrocyclic Compounds / chemical synthesis*
  • Macrocyclic Compounds / pharmacokinetics*
  • Macrocyclic Compounds / pharmacology
  • Mice
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases* / pharmacokinetics
  • Protein Kinases* / physiology
  • Structure-Activity Relationship
  • Urea / chemical synthesis*
  • Urea / pharmacokinetics*
  • Urea / pharmacology

Substances

  • Macrocyclic Compounds
  • Protein Kinase Inhibitors
  • Urea
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse