title: 7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as A2A adenosine receptor antagonists: a study on the importance of modifications at the side chain on the activity and solubility.
abstract: It was demonstrated in the early 1990s that adenosine exerts many physiological functions through the interaction with four different receptors, named A1, A2A, A2B, and A3. In the past few years, our group has been involved in the development of A2A antagonists, which led to the synthesis of SCH 58261 (1), the first potent and selective adenosine A2A antagonist, which has been widely used as a reference compound. In this paper, we present an extended series of pyrazolotriazolopyrimidines synthesized with the aim to investigate the influence of the substitutions on the pyrazole ring. The choice of the substituents was based on their capability to improve water solubility while retaining high affinity and selectivity at the human A2A adenosine receptor subtype. In this series, some structural characteristics that are important for activity, i.e., tricyclic structure, free amino group at 5-position, furan ring, and substituent at 7-position on the pyrazole moiety, have been maintained. We focused our attention on the nature of the phenyl ring substituent to improve water solubility. Following this strategy, we developed new compounds with good affinity and selectivity for A2A adenosine receptors, such as 8d (K(i) 0.12 nM; hA1/hA2A ratio = 1025; R(m) = 2.8), 8h (K(i) 0.22; hA1/hA2A ratio = 9818; R(m) = 3.4), 8i (K(i) 0.18 nM; hA1/hA2A ratio = 994; R(m) = 2.8), 8k (K(i) 0.13 nM; hA1/hA2A ratio = 4430; R(m) = 3.6), and 14b (K(i) 0.19 nM; hA1/hA2A ratio = 2273; R(m) = 2.7). All the new synthesized compounds have no significant interaction with either A2B or A3 receptor subtypes. This new series of compounds deeply enlightens some structural requirements to display high affinity and selectivity for the A2A adenosine receptor subtype, although our goal of identifying new compounds with increased water solubility was not completely achieved. On this basis, other strategies will be devised to improve this class of compounds with a profile that appears to be promising for treatment of neurodegenerative disorders, such as Parkinson's disease.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Ferrara, Via Fossato di Mortara 17/19, I-44100 Ferrara, Italy. pgb@dns.unife.it
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Barbara
authors.initials: B
authors.lastname: Cacciari
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
authors.forename: Angela
authors.initials: A
authors.lastname: Monopoli
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
mesh_terms: D001667:Binding, Competitive; D002855:Chromatography, Thin Layer; D015195:Drug Design; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D005663:Furans; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1