title: 5-Lipoxygenase inhibitors: the synthesis and structure-activity relationships of a series of 1-phenyl-3-pyrazolidinones.
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.
authors.affiliation: Department of Medicinal Chemistry, Sterling Research Group, Rensselaer, New York 12144.
authors.forename: D J
authors.initials: DJ
authors.lastname: Hlasta
authors.forename: F B
authors.initials: FB
authors.lastname: Casey
authors.forename: E W
authors.initials: EW
authors.lastname: Ferguson
authors.forename: S J
authors.initials: SJ
authors.lastname: Gangell
authors.forename: M R
authors.initials: MR
authors.lastname: Heimann
authors.forename: E P
authors.initials: EP
authors.lastname: Jaeger
authors.forename: R K
authors.initials: RK
authors.lastname: Kullnig
authors.forename: R J
authors.initials: RJ
authors.lastname: Gordon
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006168:Guinea Pigs; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles