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

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Cosimelli B,Greco G,Ehlardo M,Novellino E,Da Settimo F,Taliani S,La Motta C,Bellandi M,Tuccinardi T,Martinelli A,Ciampi O,Trincavelli ML,Martini C

doi

10.1021/jm701159t

subject

Has Abstract

pub_date

2008-03-27 00:00:00

pages

1764-70

issue

6

eissn

0022-2623

issn

1520-4804

journal_volume

51

pub_type

杂志文章

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