Synthesis and antihistaminic activity of 2-guanadino-3-cyanopyridines and pyrido[2,3-d]-pyrimidines

Bioorg Med Chem. 1997 Aug;5(8):1543-53. doi: 10.1016/s0968-0896(97)00108-9.

Abstract

2-Guanadino-3-cyanopyridines 8-33 and pyrido[2,3-d]-pyrimidines 35-52 were synthesized by nucleophilic displacement and cyclization of the chloroamidines 6a-d easily obtained by reaction of 2-aminocyanopyridines 5a-d with phosgene iminium chloride and their action on the release of histamine by mast cells examined under immunological and chemical stimulus, with and without pre-incubation. Several 2-guanadino-3-cyanopyridines and pyrido[2,3-d]-pyrimidines are shown to be inhibitors of the release of histamine when stimulated with ovoalbumin as antigen or with polymer 48/80 as chemical stimulus. Guanadino-3-cyanopyridine 30 and pyrido[2,3-d]-pyrimidine 49 are the more active of all, inhibiting the release of histamine in all the conditions tested (30-60% inhibition). Guanadinocyanopyridines 15, 17, and 19 are very potent stimulators of the release of histamine (150-300%) while pyrido[2,3-d]-pyrimidines are mostly inactive. Compounds 28 and 14 present moderate in vitro cytotoxic activity against P-388, A-549, HT-29, and MEL-28 cell lines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Histamine H1 Antagonists / chemical synthesis*
  • Histamine H1 Antagonists / pharmacology
  • Histamine Release / drug effects
  • Humans
  • Mast Cells / cytology
  • Mast Cells / drug effects
  • Models, Chemical
  • Pyridines / chemistry
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Cells, Cultured / drug effects

Substances

  • Histamine H1 Antagonists
  • Pyridines
  • Pyrimidines
  • 3-cyanopyridine