5-Lipoxygenase Inhibitors: The Synthesis and Structure-Activity Relationships of a Series of 1-phenyl-3-pyrazolidinones

J Med Chem. 1991 May;34(5):1560-70. doi: 10.1021/jm00109a006.

Abstract

A series of analogues of the 5-lipoxygenase inhibitor 1-phenyl-3-pyrazolidinone (phenidone, 1a) has been prepared via two complementary new synthetic methods. The reaction of various electrophiles with the dianion of 1a or with an N-silylpyrazolidinone anion gave the desired 4-substituted pyrazolidinones (Scheme I and II). A new procedure was developed for the resolution of 4-substituted pyrazolidinones (Scheme V). A regression study on 21 compounds in this series showed a correlation of increased inhibitor potency (pIC50) with increased compound lipophilicity (log P) and with an N-phenyl electronic effect as measured by the 13C NMR chemical shift parameter CNMR1' (R2 = 0.79). The most potent 5-lipoxygenase inhibitor in this series was 4-(ethylthio)-1-phenyl-3-pyrazolidinone (1n) with an IC50 of 60 nM. Another member of this series, 4-(2-methoxyethyl)-1-phenyl-3-pyrazolidinone (1f, IC50 = 0.48 microM), although less potent than 1n, was better tolerated in the whole animal relative to phenidone (1a) and also displayed good oral activity in two models of 5-lipoxygenase inhibition. On the basis of a structure-activity relationship study, a mechanism for the inhibition of 5-lipoxygenase by this class of inhibitors was proposed.

MeSH terms

  • Animals
  • Chemical Phenomena
  • Chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Guinea Pigs
  • Lipoxygenase Inhibitors*
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Lipoxygenase Inhibitors
  • Pyrazoles