title: The identification of the 2-phenylphthalazin-1(2H)-one scaffold as a new decorable core skeleton for the design of potent and selective human A3 adenosine receptor antagonists.
abstract: Following a molecular simplification approach, we have identified the 2-phenylphthalazin-1(2H)-one (PHTZ) ring system as a new decorable core skeleton for the design of novel hA(3) adenosine receptor (AR) antagonists. Interest for this new series was driven by the structural similarity between the PHTZ skeleton and both the 2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (TQX) and the 4-carboxamido-quinazoline (QZ) scaffolds extensively investigated in our previously reported studies. Our attention was focused at position 4 of the phthalazine nucleus where different amido and ureido moieties were introduced (compounds 2-20). Some of the new PHTZ compounds showed high hA(3) AR affinity and selectivity, the 2,5-dimethoxyphenylphthalazin-1(2H)-one 18 being the most potent and selective hA(3) AR antagonist among this series (K(i) = 0.776 nM; hA(1)/hA(3) and hA(2A)/hA(3) > 12000). Molecular docking studies on the PHTZ derivatives revealed for these compounds a binding mode similar to that of the previously reported TQX and QZ series, as was expected from the simplification approach.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Polo Scientifico, Via U. Schiff, 6-50019 Sesto Fiorentino (Firenze), Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Poli
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.forename: Guido
authors.initials: G
authors.lastname: Filacchioni
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.forename: Letizia
authors.initials: L
authors.lastname: Trincavelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity; D013379:Substrate Specificity
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D010879:Piperazines; D043684:Receptor, Adenosine A3; C031503:phenylpiperazine