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

Abstract	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.
Authors	Maria Paola Giovannoni, Claudia Vergelli, Claudio Biancalani, Nicoletta Cesari, Alessia Graziano, Pierfrancesco Biagini, Jordi Gracia, Amadeu Gavaldà, Vittorio Dal Piaz
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 17 Pg. 5363-71 (Aug 24 2006) ISSN: 0022-2623 [Print] United States
PMID	16913726 (Publication Type: Journal Article)
Chemical References	Enzyme Inhibitors Isoenzymes Pyrazoles Pyridazines Phosphoric Diester Hydrolases 3',5'-Cyclic-GMP Phosphodiesterases Cyclic Nucleotide Phosphodiesterases, Type 5 PDE5A protein, human
Topics	3',5'-Cyclic-GMP Phosphodiesterases Animals Cattle Cyclic Nucleotide Phosphodiesterases, Type 5 Enzyme Inhibitors (chemistry, pharmacology, therapeutic use) Erectile Dysfunction (drug therapy) Humans Isoenzymes (drug effects) Male Molecular Structure Phosphoric Diester Hydrolases (drug effects) Pyrazoles (chemistry, pharmacology, therapeutic use) Pyridazines (chemistry, pharmacology, therapeutic use) Stereoisomerism Structure-Activity Relationship Substrate Specificity

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