Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of farnesyl protein transferase

Bioorg Med Chem. 2003 Jan 2;11(1):139-43. doi: 10.1016/s0968-0896(02)00308-5.

Abstract

SCH 66336 is a trihalo tricyclic compound that is currently undergoing Phase II clinical trials for the treatment of solid tumors. Modifications of SCH 66336 by incorporating such groups as amides, acids, esters, ureas and lactams off the first or the distal piperidine (from the tricycle) provided potent FPT inhibitors some of which exhibited good cellular activity. A number of these compounds incorporate properties that might improve pharmacokinetic stability of these inhibitors by virtue of their increased solubility or by their change in log P.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Alkyl and Aryl Transferases / metabolism
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • COS Cells
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Kidney / cytology
  • Models, Molecular
  • Piperidines / chemistry*
  • Piperidines / pharmacology*
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Solubility
  • Structure-Activity Relationship
  • Tritium

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Piperidines
  • Pyridines
  • trihalobenzocycloheptapyridine
  • Tritium
  • Alkyl and Aryl Transferases
  • p21(ras) farnesyl-protein transferase
  • lonafarnib