Selective thromboxane synthetase inhibitors. 4. 2-(1H-imidazol-1-ylmethyl) carboxylic acids of benzo[b]furan, benzo[b]thiophene, indole, and naphthalene

J Med Chem. 1986 Sep;29(9):1643-50. doi: 10.1021/jm00159a013.

Abstract

The preparation of a series of 2-(1H-imidazol-1-ylmethyl)-substituted carboxylic acids of benzo[b]furan, benzo-[b]thiophene, indole, and naphthalene is described. All compounds showed a similar level of activity as TxA2 synthetase inhibitors in vitro, having IC50 values between 1 and 7 X 10(-8) M. In the cases examined, compounds had, at most, only negligible activity against PGI2 synthetase, cyclooxygenase, and steroid 11 beta-hydroxylase. The benzo[b]thiophenes generally showed the greatest potency in vivo, and compounds 72, 73, and 75 caused almost complete inhibition of thromboxane production for 6 h after oral administration of 0.5 mg/kg to conscious dogs. In the case of 73 and 75, thromboxane production was still inhibited by 80% after 24 h.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzofurans / pharmacology*
  • Carboxylic Acids / pharmacology*
  • Chemical Phenomena
  • Chemistry
  • Cyclooxygenase Inhibitors
  • Cytochrome P-450 Enzyme System*
  • Dogs
  • Epoprostenol / antagonists & inhibitors
  • Epoprostenol / biosynthesis
  • Imidazoles / pharmacology*
  • Indoles / pharmacology*
  • Intramolecular Oxidoreductases*
  • Male
  • Naphthalenes / pharmacology
  • Rats
  • Steroid 11-beta-Hydroxylase / antagonists & inhibitors
  • Thiophenes / pharmacology*
  • Thromboxane-A Synthase / antagonists & inhibitors*
  • Thromboxane-A Synthase / blood

Substances

  • Benzofurans
  • Carboxylic Acids
  • Cyclooxygenase Inhibitors
  • Imidazoles
  • Indoles
  • Naphthalenes
  • Thiophenes
  • Cytochrome P-450 Enzyme System
  • Epoprostenol
  • Steroid 11-beta-Hydroxylase
  • Intramolecular Oxidoreductases
  • prostacyclin synthetase
  • Thromboxane-A Synthase