title: Synthesis and biological evaluation of new phenidone analogues as potential dual cyclooxygenase (COX-1 and COX-2) and human lipoxygenase (5-LOX) inhibitors.
abstract: A new series of potential human 5-LOX inhibitors structurally related to the 1-phenyl-3-pyrazolidinone (phenidone, 2) has been synthesized and the activity against COX-1, COX-2, and human 5-LOX enzymes has been evaluated. In contrast with literature data, we observed that phenidone resulted to be inactive against human 5-LOX, while retains its activity against cyclooxygenases in a micromolar range. The present results suggest that the substitution of the amino function at the 4-position is detrimental in terms of activity toward COX-1 and COX-2, while the presence of a double bond at the 4,5-position does not alter the biological profile against COX. The absence of activity vs. human 5-LOX strongly suggests a re-consideration of phenidone and its analogs as 5-LOX inhibitors in humans.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Trieste, Piazzale Europa 1, I-34127, Trieste, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cusan
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
authors.forename: Maurizio
authors.initials: M
authors.lastname: Prato
authors.forename: Michael
authors.initials: M
authors.lastname: Adams
authors.forename: Antje
authors.initials: A
authors.lastname: Bodensieck
authors.forename: Rudolf
authors.initials: R
authors.lastname: Bauer
authors.forename: Aurelia
authors.initials: A
authors.lastname: Tubaro
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Tatiana
authors.initials: T
authors.lastname: Da Ros
mesh_terms: D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; C015429:phenidone