Synthesis and thromboxane A2/prostaglandin H2 receptor antagonistic activity of phenol derivatives

J Med Chem. 1992 Jun 12;35(12):2202-9. doi: 10.1021/jm00090a009.

Abstract

Consideration of possible structural similarities between thromboxane A2 and the hydroquinone form of (R)-(+)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7- phenylheptanoic acid (R-(+)-AA-2414) led to the development of a new series of thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonists, namely 7-(4-fluorophenyl)-7-(2-hydroxyphenyl)heptanoic acids (I). These compounds were found to be potent TXA2/PGH2 receptor antagonists. Compounds having either a carbonyl or a hydroxymethyl group at the para-position of the phenolic hydroxy group exhibited most potent activities in this series. Compounds 14, 15, 18, and 26 inhibited the specific binding of [3H]U-46619 to guinea pig platelet membranes (IC50 = 4.4, 80, 32, and 13 nM, respectively), and also inhibited U-46619-induced human platelet aggregation (IC50 = 310, 69, 79, and 78 nM, respectively). Comparison of the UV spectra of the compounds with a carbonyl group at the para-position of phenolic hydroxy group revealed that the activity tended to increase in accordance with a decrease in the torsional angle between the carbonyl group and the phenol ring. These results suggested that the spacial location of the carbonyl and hydroxymethyl oxygen are important for significant increase in activity and that the carbonyl and hydroxymethyl oxygen at the para-position of the phenolic hydroxy group might interact with one of the TXA2/PGH2 receptor sites.

Publication types

  • Comparative Study

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Animals
  • Aorta / drug effects
  • Aorta / physiology
  • Benzoquinones*
  • Blood Platelets / metabolism
  • Bronchoconstriction / drug effects
  • Cell Membrane / metabolism
  • Fluorobenzenes / chemical synthesis*
  • Fluorobenzenes / chemistry
  • Fluorobenzenes / pharmacology
  • Guinea Pigs
  • Heptanoic Acids / chemical synthesis*
  • Heptanoic Acids / chemistry
  • Heptanoic Acids / pharmacology
  • Humans
  • Hydroquinones / chemical synthesis*
  • Hydroquinones / pharmacology
  • Male
  • Molecular Structure
  • Muscle Contraction / drug effects
  • Phenols / chemical synthesis*
  • Phenols / chemistry
  • Phenols / pharmacology
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemical synthesis*
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology
  • Prostaglandin Endoperoxides, Synthetic / metabolism
  • Prostaglandin Endoperoxides, Synthetic / pharmacology
  • Quinones / chemistry*
  • Quinones / pharmacology
  • Rabbits
  • Rats
  • Rats, Inbred Strains
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Receptors, Thromboxane
  • Spectrophotometry, Ultraviolet
  • Structure-Activity Relationship

Substances

  • Benzoquinones
  • Fluorobenzenes
  • Heptanoic Acids
  • Hydroquinones
  • Phenols
  • Platelet Aggregation Inhibitors
  • Prostaglandin Endoperoxides, Synthetic
  • Quinones
  • Receptors, Prostaglandin
  • Receptors, Thromboxane
  • seratrodast
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid