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 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.
Baraldi
Pier Giovanni
PG
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara, 17/19 44100, Ferrara, Italy. pgb@dns.unife.it
Bovero
Andrea
A
Fruttarolo
Francesca
F
Romagnoli
Romeo
R
Tabrizi
Mojgan Aghazadeh
MA
Preti
Delia
D
Varani
Katia
K
Borea
Pier Andrea
PA
Moorman
Allan R
AR
D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D007536:Isomerism; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
D058918:Adenosine A3 Receptor Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; D014230:Triazoles