title: Water-soluble pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines as human A₃ adenosine receptor antagonists.
abstract: A relevant problem of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C(5) position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K(i)(hA(3)) = 9.7 nM, IC(50)(hA(3)) = 30 nM, K(i)(hA(1)/hA(3)) = 351, K(i)(hA(2A)/hA(3)) > 515, IC(50)(hA(2B)) > 5 μM) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure-activity relationships and the selectivity profile of the new ligands.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy. baraldi@unife.it
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Giulia
authors.initials: G
authors.lastname: Saponaro
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Mojgan
authors.initials: M
authors.lastname: Aghazadeh Tabrizi
authors.forename: Stefania
authors.initials: S
authors.lastname: Baraldi
authors.forename: Allan R
authors.initials: AR
authors.lastname: Moorman
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maro
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.forename: Stefania
authors.initials: S
authors.lastname: Merighi
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D011869:Radioligand Assay; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D012995:Solubility; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014867:Water
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D006575:Heterocyclic Compounds, 3-Ring; C575283:N-(1-(cyclohexylmethyl)piperidin-4-yl)-N'-(2-(2-furyl)-8-methyl-8H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-yl)urea; D043684:Receptor, Adenosine A3; D014867:Water; D014508:Urea; D000242:Cyclic AMP