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.
|Autori:||B. COSIMELLI; G. GRECO; M. EHLARDO; E. NOVELLINO; F. DA SETTIMO; S. TALIANI; LA MOTTA C; M. BELLANDI; T. TUCCINARDI; A. MARTINELLI; O. CIAMPI; M.L. TRINCAVELLI; C.MARTINI|
|Titolo:||Derivatives of 4-Amino-6-hydroxy-2-mercaptopyrimidine as Novel, Potent, and Selective A3 Adenosine Receptor Antagonists|
|Anno del prodotto:||2008|
|Digital Object Identifier (DOI):||10.1021/jm701159t|
|Appare nelle tipologie:||1.1 Articolo in rivista|