title: New strategies for the synthesis of A3 adenosine receptor antagonists.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara, 17/19 44100, Ferrara, Italy. pgb@dns.unife.it
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Andrea
authors.initials: A
authors.lastname: Bovero
authors.forename: Francesca
authors.initials: F
authors.lastname: Fruttarolo
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Allan R
authors.initials: AR
authors.lastname: Moorman
mesh_terms: 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*
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; D014230:Triazoles