title: Potent, Metabolically Stable 2-Alkyl-8-(2H-1,2,3-triazol-2-yl)-9H-adenines as Adenosine A2A Receptor Ligands.
abstract: Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson's disease (PD). We previously identified the triazolo-9H-purine, ST1535, as a potent A(2A)R antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω-1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω-1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A(2A)R was determined. Two compounds, (2-(3,3-dimethylbutyl)-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-6-amine (3 b) and 4-(6-amino-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-2-yl)-2-methylbutan-2-ol (3 c), exhibited good affinity against A(2A)R (Ki =0.4 nM and 2 nM, respectively) and high in vitro metabolic stability (89.5% and 95.3% recovery, respectively, after incubation with HLM for two hours).
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy). Silvia.Pace@sigma-tau.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pace
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy).|Present addresses: Chiesi Farmaceutici S.p.A., Parma, Italy (G.B.); Biosint S.p.A., Sermoneta, Italy (F.C.); Fresenius Kabi Anti-Infectives, Cernusco sul Naviglio, Italy (W.C.).
authors.forename: Giandomenico
authors.initials: G
authors.lastname: Brogin
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy).
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Stasi
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy).
authors.forename: Teresa
authors.initials: T
authors.lastname: Riccioni
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy).
authors.forename: Franco
authors.initials: F
authors.lastname: Borsini
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy).|Present addresses: Chiesi Farmaceutici S.p.A., Parma, Italy (G.B.); Biosint S.p.A., Sermoneta, Italy (F.C.); Fresenius Kabi Anti-Infectives, Cernusco sul Naviglio, Italy (W.C.).
authors.forename: Francesca
authors.initials: F
authors.lastname: Capocasa
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy).
authors.forename: Francesco
authors.initials: F
authors.lastname: Manera
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy).
authors.forename: Carlo
authors.initials: C
authors.lastname: Tallarico
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy).
authors.forename: Pietro
authors.initials: P
authors.lastname: Grossi
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27 A, 43124 Parma (Italy).
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27 A, 43124 Parma (Italy).
authors.forename: Michele
authors.initials: M
authors.lastname: Bassi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento 6, 61029 Urbino (PU) (Italy).
authors.forename: Francesca
authors.initials: F
authors.lastname: Bartoccini
authors.affiliation: Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento 6, 61029 Urbino (PU) (Italy).
authors.forename: Simone
authors.initials: S
authors.lastname: Lucarini
authors.affiliation: Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento 6, 61029 Urbino (PU) (Italy). giovanni.piersanti@uniurb.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piersanti
authors.affiliation: Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento 6, 61029 Urbino (PU) (Italy).
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy).|Present addresses: Chiesi Farmaceutici S.p.A., Parma, Italy (G.B.); Biosint S.p.A., Sermoneta, Italy (F.C.); Fresenius Kabi Anti-Infectives, Cernusco sul Naviglio, Italy (W.C.).
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
authors.affiliation: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km 30, 400, 00040 Pomezia (Italy).
authors.forename: Patrizia
authors.initials: P
authors.lastname: Minetti
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism*
chemical_list: C000606488:2-(3,3-dimethylbutyl)-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-6-amine; C000606489:4-(6-amino-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-2-yl)-2-methylbutan-2-ol; D008024:Ligands; D043705:Receptor, Adenosine A2A; D014230:Triazoles; D000241:Adenosine
keywords: Parkinson’s disease; adenosine A2a receptors; drug discovery; metabolic stability; purines