1,3-Diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives: a new series of potent and selective COX-2 inhibitors in which a sulfonyl group is not a structural requisite

J Med Chem. 2000 Nov 30;43(24):4582-93. doi: 10.1021/jm990965x.

Abstract

Novel tetrahydro-2H-isoindoles have been prepared and evaluated as inhibitors of the COX-2 isoenzyme. A 1,3-diaryl substitution on the central polycyclic ring system and absence of a sulfonyl moiety are the two structural features of this chemical series. A short and easy synthetic pathway produced several derivatives which were shown to be potent and selective COX-2 vs COX-1 inhibitors (IC(50) = 0. 6-100 nM for COX-2, 100->1000 nM for COX-1). Structural modifications established that a bicyclic ring appended to the pyrrole nucleus and 4,4'-difluoro substitution on the phenyl rings were optimal for high inhibitory potency. Activity was confirmed in the human whole blood assay and subsequently in the murine air-pouch model in which in vivo PGE2 inhibitory activity was evaluated with respect to gastric tolerance (ED(50) for inhibition of exudate PGE2 of 3 mg/kg and gastric PGE2 of 20 mg/kg). Gastric tolerance was further assessed after administration to mice of high doses (up to 400 mg/kg) of the inhibitors by measurement of gastric damage. This panel of studies allowed selection of a number of tetrahydro-2H-isoindoles which were compared in the adjuvant-induced arthritis model. Compounds 32 and 37 showed the most potent activity with ED(50) values for edema inhibition in the noninjected paw of 0. 35 and 0.15 mg/kg/day, respectively, after oral administration. In addition, this interesting antiinflammatory profile was accompanied by a protective effect against arthritis-induced osteopenia, the decrease being 50% with a dose of 0.25 mg/kg/day.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / toxicity
  • Arthritis, Experimental / drug therapy
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology
  • Cyclooxygenase Inhibitors / toxicity
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Heterocyclic Compounds, 3-Ring / toxicity
  • Humans
  • In Vitro Techniques
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Indoles / toxicity
  • Isoenzymes / antagonists & inhibitors*
  • Macrophages, Peritoneal / enzymology
  • Membrane Proteins
  • Mice
  • Prostaglandin-Endoperoxide Synthases
  • Stomach / drug effects
  • Stomach / pathology
  • Structure-Activity Relationship

Substances

  • 3,5-bis(4-fluorophenyl)-4--azatricyclo(5.2.2.0(2,6))undeca-2,5-diene
  • 3,5-bis(4-fluorophenyl)-4-azatricyclo(5.2.1.0(2,6))deca-2,5-diene
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Indoles
  • Isoenzymes
  • Membrane Proteins
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, mouse