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J Med Chem. 2008 Mar 27;51(6):1764-70. doi: 10.1021/jm701159t. Epub 2008 Feb 13.

Derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine as novel, potent, and selective A3 adenosine receptor antagonists.

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Departimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Via D. Montesano 49, Naples, Italy.


A number of derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine ( 5) were synthesized and biologically evaluated as A 3 adenosine receptor (A 3 AR) antagonists. The new compounds were designed as open chain analogues of a triazolopyrimidinone derivative displaying submicromolar affinity for the A 3 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 A 3 AR binding site. As a result, 5m (R = n-C 3H 7, R' = 4-ClC 6H 4CH 2, R'' = CH 3) 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 A 3 AR with a K i of 3.5 nM and is devoid of appreciable affinity for the A 1, A 2A, and A 2B ARs.

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