title: 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.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy. mariapaola.giovannoni@unifi.it
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Biancalani
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Cesari
authors.forename: Alessia
authors.initials: A
authors.lastname: Graziano
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Biagini
authors.forename: Jordi
authors.initials: J
authors.lastname: Gracia
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.forename: Vittorio
authors.initials: V
authors.lastname: Dal Piaz
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D002417:Cattle; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D011724:Pyridazines; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human