Evaluation of amino acid-based linkers in potent macrocyclic inhibitors of farnesyl-protein transferase

Bioorg Med Chem Lett. 2001 Jul 23;11(14):1817-21. doi: 10.1016/s0960-894x(01)00340-7.

Abstract

A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Alkyl and Aryl Transferases / drug effects*
  • Amino Acids / chemistry
  • Animals
  • Cells, Cultured
  • Dogs
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacokinetics*
  • Half-Life
  • Inhibitory Concentration 50
  • Metabolic Clearance Rate / physiology
  • Molecular Conformation
  • Protein Binding / drug effects
  • Rats

Substances

  • Amino Acids
  • Enzyme Inhibitors
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • p21(ras) farnesyl-protein transferase