title: Functionalized pyrazoles and pyrazolo[3,4-d]pyridazinones: Synthesis and evaluation of their phosphodiesterase 4 inhibitory activity.
abstract: A series of pyrazoles and pyrazolo[3,4-d]pyridazinones were synthesized and evaluated for their PDE4 inhibitory activity. All the pyrazoles were found devoid of activity, whereas some of the novel pyrazolo[3,4-d]pyridazinones showed good activity as PDE4 inhibitors. The most potent compounds in this series showed an IC(50) in the nanomolar range. The ability to inhibit TNF-alpha release in human PBMCs was determined for two representative compounds, finding values in the sub-micromolar range. SARs studies demonstrated that the best arranged groups around the heterocyclic core are 2-chloro-, 2-methyl- and 3-nitrophenyl at position 2, an ethyl ester at position 4 and a small alkyl group at position 6. Molecular modeling studies performed on a representative compound allowed to define its binding mode to the PDE4B isoform.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Biagini
authors.forename: Claudio
authors.initials: C
authors.lastname: Biancalani
authors.forename: Alessia
authors.initials: A
authors.lastname: Graziano
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Cesari
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.forename: Vittorio
authors.initials: V
authors.lastname: Dal Piaz
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
authors.forename: Letizia
authors.initials: L
authors.lastname: Crocetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Delcanale
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Armani
authors.forename: Andrea
authors.initials: A
authors.lastname: Rizzi
authors.forename: Paola
authors.initials: P
authors.lastname: Puccini
authors.forename: Paola Maria
authors.initials: PM
authors.lastname: Gallo
authors.forename: Daniele
authors.initials: D
authors.lastname: Spinabelli
authors.forename: Paola
authors.initials: P
authors.lastname: Caruso
mesh_terms: D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D014409:Tumor Necrosis Factor-alpha