(Pyridylcyanomethyl)piperazines as orally active PAF antagonists

J Med Chem. 1992 Oct 30;35(22):4118-34. doi: 10.1021/jm00100a018.


A series of (pyridylcyanomethyl)piperazines was prepared and evaluated for PAF-antagonist activity. Compounds were tested in vitro in a PAF-induced platelet aggregation assay and in vivo in a PAF-induced hypotension test in normotensive rats. Oral activity was ascertained through a PAF-induced mortality test in mice. The main structure-activity trends of the series were established. Activity was mainly found in four skeletons: 1-acyl-4-(3-pyridylcyanomethyl)piperazine, 1-acyl-4-(4-pyridylcyanomethyl)piperazine, 1-acyl-4-(3-pyridylcyanomethyl)piperidine, and 1-acyl-4-cyano-4-(3-pyridylamino)piperidine. The acyl substituents, diphenylacetyl and 3,3-diphenylpropionyl, provided the most active compounds, and the introduction of an amine or hydroxy group in the 3,3-diphenylpropionyl substituent led to further improvement in oral activity. As a result, three of the most active compounds (100, 114, and 115) have been selected for further pharmacological development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Blood Pressure / drug effects
  • In Vitro Techniques
  • Male
  • Mice
  • Piperazines / administration & dosage
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Piperidines / administration & dosage
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology
  • Platelet Activating Factor / antagonists & inhibitors*
  • Platelet Aggregation / drug effects
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship


  • Piperazines
  • Piperidines
  • Platelet Activating Factor