- Derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine as novel, potent, and selective A3 adenosine receptor antagonists
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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-C3H 7, 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 Ki of 3.5 nM and is devoid of appreciable affinity for the A1, A 2A, and A2B ARs.
- 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
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p. 1764 - 1770
(2008/12/22)
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