Synthesis and evaluation of some pyrazolo[3,4-d]pyridazinones and analogues as PDE 5 inhibitors potentially useful as peripheral vasodilator agents.
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.
Dal Piaz
Vittorio
V
Dipartimento di Scienze Farmaceutiche, Via G. Capponi 9, 50121 Firenze, Italy. vittorio.dalpiaz@unifi.it
Castellana
Maria Carla
MC
Vergelli
Claudia
C
Giovannoni
Maria Paola
MP
Gavaldà
Amadeu
A
Segarra
Victor
V
Beleta
Jorge
J
Ryder
Hamish
H
Palacios
Josè Maria
JM
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
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