Design and synthesis of indomethacin analogues that inhibit P-glycoprotein and/or multidrug resistant protein without COX inhibitory activity

J Med Chem. 2012 Sep 27;55(18):8152-63. doi: 10.1021/jm301084z. Epub 2012 Sep 6.

Abstract

We designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug resistance indicated that NSAIDS modulation of multidrug-resistant P-glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology
  • Drug Design*
  • Drug Resistance, Multiple / drug effects
  • Humans
  • Indomethacin / analogs & derivatives
  • Indomethacin / chemical synthesis*
  • Indomethacin / chemistry
  • Indomethacin / pharmacology*
  • Models, Molecular
  • Molecular Conformation
  • Prostaglandin-Endoperoxide Synthases / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase Inhibitors
  • Prostaglandin-Endoperoxide Synthases
  • Indomethacin