Rational design of 6-methylsulfonylindoles as selective cyclooxygenase-2 inhibitors

Bioorg Med Chem Lett. 2004 Sep 20;14(18):4741-5. doi: 10.1016/j.bmcl.2004.06.075.

Abstract

The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Carrageenan
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology*
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Inflammation / chemically induced
  • Inflammation / prevention & control
  • Membrane Proteins
  • Models, Molecular
  • Prostaglandin-Endoperoxide Synthases / blood
  • Rats
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology

Substances

  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Indoles
  • Membrane Proteins
  • Sulfones
  • Carrageenan
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases