Synthesis and in vitro activity of stereoisomers of a novel thromboxane receptor antagonist, (+-)-(5Z)-7-[3-endo-[(phenylsulfonyl)amino]bicyclo [2.2.1]hept-2-exo-yl]heptenoic acid

J Med Chem. 1990 Mar;33(3):1027-31. doi: 10.1021/jm00165a022.

Abstract

Three stereoisomers of S-145 (1) with variations at the side-chain junctions were synthesized. Endo-cis isomer 10 and N-exo-trans isomer 18 were obtained via the common intermediate 5 having an endo-fused ring structure. Exo-cis isomer 28 was prepared via exo-fused azetidino compound 21. Inhibitory concentrations (IC50) of the sodium salts newly obtained for platelet aggregation were measured using washed rat platelets (WP) and human platelet-rich plasma (PRP). The IC50 values of these compounds for contraction of the rat aorta were also measured. Compound 1 of N-endo-trans structure and N-exo-trans isomer 18 exhibited more potent inhibitory activity than cis-isomers 10 and 28 against responses induced by TXA2-related substances for rat WP and rat thoracic aorta. However, these compounds exhibited almost comparable inhibitory activity for human PRP.

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / pharmacology
  • Bridged-Ring Compounds / chemical synthesis*
  • Fatty Acids, Monounsaturated / chemical synthesis*
  • Fatty Acids, Monounsaturated / pharmacology
  • Humans
  • In Vitro Techniques
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemical synthesis
  • Platelet Aggregation Inhibitors / pharmacology
  • Rats
  • Receptors, Prostaglandin / drug effects*
  • Receptors, Thromboxane
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thromboxane A2 / antagonists & inhibitors*

Substances

  • Bridged Bicyclo Compounds
  • Bridged-Ring Compounds
  • Fatty Acids, Monounsaturated
  • Platelet Aggregation Inhibitors
  • Receptors, Prostaglandin
  • Receptors, Thromboxane
  • S 145
  • Thromboxane A2