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

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-03, Vol.51 (6), p.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: Article
Language:English
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm701159t