1,4-Dihydropyridines as antagonists of platelet activating factor. 1. Synthesis and structure-activity relationships of 2-(4-heterocyclyl)phenyl derivatives

J Med Chem. 1992 Aug 21;35(17):3115-29. doi: 10.1021/jm00095a005.


A novel class of 2-(4-heterocyclylphenyl)-1,4-dihydropyridines (2-38) possessing antagonist activity against platelet activating factor (PAF) was prepared by the Hantzsch synthesis from a variety of ethyl 4'-heterocyclic-substituted benzoylacetates, aryl or heteroaryl aldehydes, and substituted 3-aminocrotonamides or 3-aminocrotonate esters. Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit the PAF-induced aggregation of rabbit washed platelets, and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF. The nature of the substituent at the dihydropyridine 2-position was found to be important for both in vitro and in vivo activity, whereas there was greater flexibility for structural variation at the 4- and 5-positions. The most potent compound was 4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl-2-[4-(2- methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5-[N-(2- pyridyl)carbamoyl]pyridine (17, UK-74,505), IC50 = 4.3 nM, ED50 = 0.26 mg/kg po, which was found to be approximately 33 times more potent in vitro (rabbit platelet aggregation) and about 8 times more potent in vivo (murine lethality) than WEB2086. Compound 17 also exhibited a long duration of action in the dog (inhibition of PAF-induced whole blood aggregation ex vivo was maintained for greater than 24 h following a single oral dose of 75 micrograms/kg) and was highly selective as a PAF antagonist, showing only weak affinity (IC50 = 6600 nM) for the [3H]nitrendipine binding site. As a result of its high oral potency, selectivity, and duration of action, UK-74,505 has been selected for clinical evaluation.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Dihydropyridines / chemical synthesis
  • Dihydropyridines / chemistry
  • Dihydropyridines / pharmacology*
  • Dogs
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Mice
  • Molecular Structure
  • Platelet Activating Factor / antagonists & inhibitors*
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemical synthesis
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology*
  • Rabbits
  • Structure-Activity Relationship


  • Dihydropyridines
  • Imidazoles
  • Platelet Activating Factor
  • Platelet Aggregation Inhibitors
  • modipafant