Functionalized pyrazoles and pyrazolo[3,4-d]pyridazinones: Synthesis and evaluation of their phosphodiesterase 4 inhibitory activity.
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.
Biagini
Pierfrancesco
P
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
Biancalani
Claudio
C
Graziano
Alessia
A
Cesari
Nicoletta
N
Giovannoni
Maria Paola
MP
Cilibrizzi
Agostino
A
Dal Piaz
Vittorio
V
Vergelli
Claudia
C
Crocetti
Letizia
L
Delcanale
Maurizio
M
Armani
Elisabetta
E
Rizzi
Andrea
A
Puccini
Paola
P
Gallo
Paola Maria
PM
Spinabelli
Daniele
D
Caruso
Paola
P
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
D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D014409:Tumor Necrosis Factor-alpha