Structure-activity studies on triazolothienodiazepine derivatives as platelet-activating factor antagonists

Chem Pharm Bull (Tokyo). 1991 Dec;39(12):3215-20. doi: 10.1248/cpb.39.3215.

Abstract

A series of triazolodiazepines was synthesized and evaluated for anti-platelet activating factor (PAF) activities. Structure-activity relationship (SAR) studies on this series revealed that the introduction of a methyl group into the 8-position of the thienodiazepine nucleus can lead to a lengthening of the duration of action. Introduction of a methyl group produced an asymmetric center and the enantiomers so formed were separated with an optical resolving column. In the in vitro assay system, the (+)-isomers displayed 50-200 times more potent anti-PAF activity than the (-)-isomers. After comparison of toxicology and pharmacokinetics, (+)-6-(2-chlorophenyl)-3- cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4' ,3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (35(+)-isomer, E6123) was selected from among the compounds synthesized as a candidate for clinical study.

MeSH terms

  • Animals
  • Azepines / chemical synthesis*
  • Azepines / pharmacology
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Platelet Activating Factor / antagonists & inhibitors*
  • Platelet Activating Factor / metabolism
  • Platelet Activation / drug effects
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / pharmacology

Substances

  • Azepines
  • Platelet Activating Factor
  • Triazoles
  • E 6123