Thromboxane synthase inhibitors. Synthesis and pharmacological activity of (R)-, (S)-, and (+/-)-2,2-dimethyl-6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)- methoxy]methyl]ethoxy]hexanoic acids

J Med Chem. 1987 Oct;30(10):1812-8. doi: 10.1021/jm00393a022.

Abstract

A series of substituted omega-[2-(1H-imidazol-1-yl)ethoxy]alkanoic acid derivatives were synthesized and evaluated for their ability to inhibit thromboxane synthase both in vitro and in vivo. Compound 13 was identified as a potent and selective competitive inhibitor of human platelet thromboxane synthase having a Ki value of 9.6 X 10(-8) M. In collagen-treated human whole blood, 13 potentiated levels of 6-keto PGF1 alpha. Enantiospecific syntheses afforded the R and S enantiomers of 13, of which the S enantiomer 13b was the more potent. Compounds 13 and 13b were potent in vivo inhibitors of thromboxane synthase with good oral activity and duration of action.

MeSH terms

  • 6-Ketoprostaglandin F1 alpha / blood
  • Administration, Oral
  • Animals
  • Caproates / chemical synthesis*
  • Caproates / pharmacology
  • Collagen / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Guinea Pigs
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacology
  • Kinetics
  • Prostaglandin Endoperoxides, Synthetic / metabolism
  • Prostaglandin H2
  • Prostaglandins H / metabolism
  • Stereoisomerism
  • Thromboxane B2 / blood
  • Thromboxane-A Synthase / antagonists & inhibitors*

Substances

  • Caproates
  • Enzyme Inhibitors
  • Imidazoles
  • Prostaglandin Endoperoxides, Synthetic
  • Prostaglandins H
  • Prostaglandin H2
  • Thromboxane B2
  • 6-Ketoprostaglandin F1 alpha
  • Collagen
  • Thromboxane-A Synthase