New strategies for the synthesis of A3 adenosine receptor antagonists

New A(3) adenosine receptor antagonists were synthesized and tested at human adenosine receptor subtypes. An advanced synthetic strategy permitted us to obtain a large amount of the key intermediate 5 that was then submitted to alkylation procedures in order to obtain the derivatives 6-8. These comp...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2003-09, Vol.11 (19), p.4161-4169
Main Authors: BARALDI, Pier Giovanni, BOVERO, Andrea, FRUTTAROLO, Francesca, ROMAGNOLI, Romeo, MOJGAN AGHAZADEH TABRIZI, PRETI, Delia, VARANI, Katia, BOREA, Pier Andrea, MOORMAN, Allan R
Format: Article
Language:English
Subjects:
Adenosine A3 Receptor Antagonists
Animals
Binding, Competitive
Biological and medical sciences
CHO Cells
Cricetinae
Drug Design
Humans
Isomerism
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Pyrazoles - chemistry
Pyrimidines - chemical synthesis
Pyrimidines - metabolism
Pyrimidines - pharmacology
Receptor, Adenosine A3 - metabolism
Structure-Activity Relationship
Triazoles - chemistry
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Summary:New A(3) adenosine receptor antagonists were synthesized and tested at human adenosine receptor subtypes. An advanced synthetic strategy permitted us to obtain a large amount of the key intermediate 5 that was then submitted to alkylation procedures in order to obtain the derivatives 6-8. These compounds were then functionalised into ureas at the 5-position (compounds 9-11, 18 and 19) to evaluate their affinity and selectivity versus hA(3) adenosine receptor subtype; in particular, compounds 18 and 19 displayed a value of affinity of 4.9 and 1.3 nM, respectively. Starting from 5, the synthetic methodologies employed permitted us to perform a rapid and a convenient divergent synthesis. A further improvement allowed the regioselective preparation of the N(8)-substituted compound 7. This method could be used as an helpful general procedure for the design of novel A(3) adenosine receptor antagonists without the difficulty of separating the N(8)-substituted pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines from the corresponding N(7)-isomers.
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(03)00484-X