5-lipoxygenase inhibitors: The synthesis and structure-activity relationships of a series of 1-phenyl-3-pyrazolidinones

Article abstract of DOI:10.1021/jm00109a006

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 μM), 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.