Derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine as novel, potent, and selective A3 adenosine receptor antagonists.
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.
Cosimelli
Barbara
B
Departimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Via D. Montesano 49, Naples, Italy. barbara.cosimelli@unina.it
Greco
Giovanni
G
Ehlardo
Marina
M
Novellino
Ettore
E
Da Settimo
Federico
F
Taliani
Sabrina
S
La Motta
Concettina
C
Bellandi
Marusca
M
Tuccinardi
Tiziano
T
Martinelli
Adriano
A
Ciampi
Osele
O
Trincavelli
Maria Letizia
ML
Martini
Claudia
C
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D011743:Pyrimidines; D013438:Sulfhydryl Compounds