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.

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

DA SETTIMO PASSETTI, FEDERICO;TALIANI, SABRINA;LA MOTTA, CONCETTINA;TUCCINARDI, TIZIANO;MARTINELLI, ADRIANO;TRINCAVELLI, MARIA LETIZIA;MARTINI, CLAUDIA
2008

Abstract

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.
B., Cosimelli; G., Greco; M., Ehlardo; E., Novellino; DA SETTIMO PASSETTI, Federico; Taliani, Sabrina; LA MOTTA, Concettina; M., Bellandi; Tuccinardi, Tiziano; Martinelli, Adriano; O., Ciampi; Trincavelli, MARIA LETIZIA; Martini, Claudia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/195246
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