Chiral resolution and absolute configuration of the enantiomers of 5-acetyl-2-methyl-4-methylsulfinyl-6-phenyl-3(2H)-pyridazinone and evaluation of their platelet aggregation inhibitory activity

Chirality. 1997;9(7):681-5. doi: 10.1002/(SICI)1520-636X(1997)9:7<681::AID-CHIR8>3.0.CO;2-A.

Abstract

In a series of 5-acyl-6-phenyl-2,4-substituted-3(2H)-pyridaziones the derivative 1a, with a sulfur stereogenic center, had the most potent activity as human platelet aggregation inhibitor. The resolution of rac-1a was successfully performed by chiral chromatography on Chiralcel OD-R, OD-H, and Chiralpak AD columns and scaled up to a preparative level. The absolute configuration of (-)-(S)-1a was determined by X-ray crystallographic analysis. In vitro human platelet aggregation inhibitory activity was evaluated. Both the enantiomers showed IC50 values in the same micromolar range, but the (-)-(S) isomer was slightly more potent [(S)/(R) potency ratio was 4/1].

MeSH terms

  • Chromatography, High Pressure Liquid
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Humans
  • In Vitro Techniques
  • Models, Molecular
  • Molecular Conformation
  • Platelet Aggregation Inhibitors / chemistry*
  • Platelet Aggregation Inhibitors / pharmacology*
  • Pyridazines* / chemistry*
  • Pyridazines* / isolation & purification
  • Pyridazines* / pharmacology*
  • Stereoisomerism

Substances

  • Platelet Aggregation Inhibitors
  • Pyridazines