Kinesin spindle protein (KSP) inhibitors. Part 7: Design and synthesis of 3,3-disubstituted dihydropyrazolobenzoxazines as potent inhibitors of the mitotic kinesin KSP

Bioorg Med Chem Lett. 2007 Oct 15;17(20):5671-6. doi: 10.1016/j.bmcl.2007.07.067. Epub 2007 Aug 21.

Abstract

Observations from two structurally related series of KSP inhibitors led to the proposal and discovery of dihydropyrazolobenzoxazines that possess ideal properties for cancer drug development. The synthesis and characterization of this class of inhibitors along with relevant pharmacokinetic and in vivo data are presented. The synthesis is highlighted by a key [3+2] cycloaddition to form the pyrazolobenzoxazine core followed by diastereospecific installation of a quaternary center.

MeSH terms

  • Animals
  • Benzoxazines / chemical synthesis
  • Benzoxazines / chemistry*
  • Benzoxazines / pharmacokinetics
  • Benzoxazines / pharmacology*
  • Cell Line
  • Dogs
  • Drug Design*
  • Humans
  • Hydrogen / chemistry
  • Kinesin / antagonists & inhibitors*
  • Kinesin / metabolism*
  • Mitosis / drug effects*
  • Molecular Structure
  • Pyrazoles / chemistry*
  • Structure-Activity Relationship

Substances

  • Benzoxazines
  • Pyrazoles
  • pyrazole
  • Hydrogen
  • Kinesin