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Novel pyrazolopyrimidopyridazinones with potent and selective phosphodiesterase 5 (PDE5) inhibitory activity as potential agents for treatment of erectile dysfunction.

Giovannoni MP, Vergelli C, Biancalani C, Cesari N, Graziano A, Biagini P, Gracia J, Gavaldà A, Dal Piaz V

Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy. mariapaola.giovannoni@unifi.it

Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones and their analogues, potentially useful for the treatment of erectile dysfunction, were synthesized and evaluated as inhibitors of phosphodiesterase 5 (PDE5). Several compounds showed IC50 values in the low nanomolar range, and in particular, compound 5r, displaying high potency toward PDE5 (IC50 = 8.3 nM) and high selectivity versus PDE6 (240-fold) appeared to be a very promising new lead both in comparison with the potent but not selective sildenafil and in comparison with some analogues previously reported by us. SAR studies in this triheterocyclic scaffold led us to conclude that the best arranged groups are a methyl in position 1, a benzyl in position 3, a phenyl in position 9, and a linear four-carbon chain in position 6.

Published 17 August 2006 in J Med Chem, 49(17): 5363-71.
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