Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases

J Med Chem. 2006 Mar 9;49(5):1668-83. doi: 10.1021/jm0510474.

Abstract

A group of 1,3-diarylprop-2-yn-1-ones (13, 17, 23, 26 and 27) possessing a C-3 p-SO2Me COX-2 pharmacophore were designed, synthesized and evaluated as potential dual inhibitors of cyclooxygenase-1/2 (COX-1/2) and 5/15-lipoxygenases (5/15-LOX) that exhibit vivo antiinflammatory and analgesic activities. Among this class of compounds, 3-(4-methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-one (13h) was identified as a potent and selective inhibitor of COX-2 (COX-2 IC50 = 0.1 microM; SI = 300), being 5-fold more potent than rofecoxib (COX-2 IC50 = 0.5 microM; SI > 200). In a rat carrageenan-induced paw edema assay 13h exhibited moderate antiinflammatory activity (26% inhibition of inflammation) at 3 h after administration of a 30 mg/kg oral dose. A related dual COX-1/2 and 5/15-LOX inhibitor 3-(4-methanesulfonylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-one (13g, COX-1 IC50 = 31.5 microM; COX-2 IC50 = 1.0 microM; SI = 31.5; 5-LOX IC50 = 1.0 microM; 15-LOX IC50 = 3.2 microM) exhibited more potent antiinflammatory activity (ED50 = 90 mg/kg), being superior to the reference drug aspirin (ED50 = 129 mg/kg). Within this group of compounds 3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e) emerged as having an optimal combination of in vitro COX-1/2 and 5/15-LOX inhibitory effects (COX-1 IC50 = 9.2 microM; COX-2 IC50 = 0.32 microM; SI = 28; 5-LOX IC50 = 0.32 microM; 15-LOX IC50 = 0.36 microM) in conjunction with a good antiinflammatory activity (ED50 = 35 mg/kg) compared to the reference drug celecoxib (ED50 = 10.8 mg/kg) when administered orally. A molecular modeling study where 13e was docked in the COX-2 binding site indicated the C-1 p-i-Pr group was positioned within a hydrophobic pocket (Phe205, Val344, Val349, Phe381 and Leu534), and that this positioning of the i-Pr group facilitated orientation of the C-3 p-SO2Me COX-2 pharmacophore such that it inserted into the COX-2 secondary pocket (His90, Arg513, Ile517 and Val523). A related docking study of 13e in the 15-LOX binding site indicates that the C-3 p-SO2Me COX-2 pharmacophore was positioned in a region closer to the catalytic iron site where it undergoes a hydrogen bonding interaction with His541 and His366, and that the C-1 p-i-Pr substituent is buried deep in a hydrophobic pocket (Ile414, Ile418, Met419 and Ile593) near the base of the 15-LOX binding site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Alkynes / chemical synthesis*
  • Alkynes / chemistry
  • Alkynes / pharmacology
  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Arachidonate 15-Lipoxygenase / chemistry
  • Carrageenan
  • Cyclooxygenase 1 / chemistry
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / chemistry
  • Cyclooxygenase 2 Inhibitors / chemical synthesis
  • Cyclooxygenase 2 Inhibitors / chemistry
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology
  • Edema / chemically induced
  • Edema / drug therapy
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology
  • Mice
  • Models, Molecular
  • Pain Measurement
  • Rats
  • Structure-Activity Relationship

Substances

  • Alkynes
  • Analgesics
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Lipoxygenase Inhibitors
  • methylacetylene
  • Carrageenan
  • Arachidonate 15-Lipoxygenase
  • Cyclooxygenase 1
  • Cyclooxygenase 2