New strategies for the synthesis of A3 adenosine receptor antagonists

• 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
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(03)00484-X

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.