Derivatives of 4-Amino-6-hydroxy-2-mercaptopyrimidine as Novel, Potent, and Selective A3 Adenosine Receptor Antagonists

• Published in: Journal of medicinal chemistry Vol. 51; no. 6; pp. 1764 - 1770
• Main Authors: Cosimelli, Barbara, Greco, Giovanni, Ehlardo, Marina, Novellino, Ettore, Da Settimo, Federico, Taliani, Sabrina, La Motta, Concettina, Bellandi, Marusca, Tuccinardi, Tiziano, Martinelli, Adriano, Ciampi, Osele, Trincavelli, Maria Letizia, Martini, Claudia
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 27.03.2008
• Subjects: Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Adenosine A3 Receptor Antagonists; Animals; Binding Sites; Binding, Competitive - drug effects; Biological and medical sciences; CHO Cells; Computer Simulation; Cricetinae; Cricetulus; Drug Design; Humans; Ligands; Medical sciences; Models, Molecular; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Stereoisomerism; Structure-Activity Relationship; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - pharmacology; Human; Nitrogen heterocycle; Benzene derivatives; Selectivity; In vitro; A3 adenosine receptor; Structure activity relation; Chlorine Organic compounds; Six membered ring; Affinity; Carboxamide; Pyrimidine derivatives; Antagonist
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm701159t

A number of derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine (5) were synthesized and biologically evaluated as A3 adenosine receptor (A3 AR) antagonists. The new compounds were designed as open chain analogues of a triazolopyrimidinone derivative displaying submicromolar affinity for the A3 AR, which had been previously identified using a 3D database search. Substituents R, R′, and R′′ attached to the parent compound 5 were chosen according to factorial design and stepwise lead optimization approaches, taking into account the essentially hydrophobic nature of the A3 AR binding site. As a result, 5m (R = n-C3H7, R′ = 4-ClC6H4CH2, R′′ = CH3) was identified among the pyrimidine derivatives as the ligand featuring the best combination of potency and selectivity for the target receptor. This compound binds to the A3 AR with a K i of 3.5 nM and is devoid of appreciable affinity for the A1, A2A, and A2B ARs.