title: Synthesis and evaluation of some pyrazolo[3,4-d]pyridazinones and analogues as PDE 5 inhibitors potentially useful as peripheral vasodilator agents.
abstract: A series of pyrazolo[3,4-d]pyridazinones and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed IC50 values in the range 0.14-1.4 microM. A good activity and selectivity profile versus PDE6 was found for compound 11e (6-benzyl-3-methyl-1-isopropyl-4-phenylpyrazolo[3,4-d] pyridazin-7(6H)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position-6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five and six membered heterocycles (pyrrole, isoxazole, pyridine and dihydropyridine), as well as some open models were prepared and evaluated. Besides the pyrazole, the best fused systems proved to be isoxazole and pyridine.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Via G. Capponi 9, 50121 Firenze, Italy. vittorio.dalpiaz@unifi.it
authors.forename: Vittorio
authors.initials: V
authors.lastname: Dal Piaz
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Castellana
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.forename: Victor
authors.initials: V
authors.lastname: Segarra
authors.forename: Jorge
authors.initials: J
authors.lastname: Beleta
authors.forename: Hamish
authors.initials: H
authors.lastname: Ryder
authors.forename: Josè Maria
authors.initials: JM
authors.lastname: Palacios
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D001792:Blood Platelets / Q000201:enzymology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D006801:Humans; D020128:Inhibitory Concentration 50; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D014665:Vasodilator Agents; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517381:PDE5A protein, human; C517431:PDE6B protein, human