Computer-aided molecular modeling of a thromboxane receptor antagonist S-145 and its related compounds

J Med Chem. 1990 Apr;33(4):1117-22. doi: 10.1021/jm00166a006.

Abstract

Conformational analyses on thromboxane A2 (TxA2), its receptor agonist, U-46619, and its receptor antagonist, sulotroban, were carried out by molecular mechanics (MMFF) or molecular orbital (MNDO) methods. Two kinds of putative active conformations of TxA2 and the agonist were proposed on the basis of these results by referring to the hairpin conformation hypothesis. From the superposition of stable conformers of sulotroban on those conformers, the molecular structural requirements for potent TxA2 receptor antagonism were elucidated. S-145 in which these requirements are satisfied was a very potent TxA2 antagonist.

Publication types

  • Comparative Study

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Bridged Bicyclo Compounds* / pharmacology
  • Bridged-Ring Compounds* / pharmacology
  • Computer Simulation*
  • Fatty Acids, Monounsaturated* / pharmacology
  • Models, Molecular
  • Molecular Conformation
  • Prostaglandin Endoperoxides, Synthetic* / pharmacology
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Receptors, Thromboxane
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides* / pharmacology
  • Thromboxane A2* / antagonists & inhibitors
  • Thromboxane A2* / pharmacology

Substances

  • Bridged Bicyclo Compounds
  • Bridged-Ring Compounds
  • Fatty Acids, Monounsaturated
  • Prostaglandin Endoperoxides, Synthetic
  • Receptors, Prostaglandin
  • Receptors, Thromboxane
  • Sulfonamides
  • S 145
  • Thromboxane A2
  • sulotroban
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid