Design, synthesis, and biological evaluation of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as new A2A and A3 adenosine receptors antagonists.
In the past few years, our group has been involved in the development of A(2A) and A(3) adenosine receptor antagonists which led to the synthesis of SCH58261 (5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, 61), potent and very selective at the A(2A) receptor subtype, and N(8)-substituted-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines-N(5)-urea or amide (MRE series, b), very selective at the human A(3) adenosine receptor subtype. We now describe a large series of C(9)- and C(2)-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines to represent an extension of structure-activity relationship work on this class of tricyclic compounds. The introduction of a substituent at 9 position of the tricyclic antagonistic structure led to retention of receptor affinity but a loss of selectivity in respect to the lead compounds b, N(8)-substituted-pirazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines-N(5)-urea or -amide. The substitution of the furanyl moiety of compound 61, necessary for receptor binding, with a phenyl or a substituted aromatic ring (compounds 5a-d, 6-8), caused a complete loss of the affinity at all the adenosine receptor subtypes, demonstrating that the furanyl ring is a necessary structural element to guarantee interaction with the adenosine receptor surface. The introduction of an ethoxy group at the ortho position of the aromatic ring to mimic the oxygen of the furan (compound 5c, 5-amino-7-(2-phenylethyl)-2-(2-ethoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) did not enhance affinity. The introduction of the cycloaminomethyl function by Mannich reaction at the 5' position of the furanyl ring of 61 and the C(9)-substituted compound 41 (5-amino-8-methyl-9-methylsulfanyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) resulted in complete water solubility but a loss of receptor affinity. We can conclude that modifications or substitutions at the furanyl ring are not allowed and the introduction of a substituent at the 9-position of the core pyrazolo-triazolo-pyrimidine structure caused a severe loss of selectivity, probably due to an increased steric hindrance of the radical introduced.
Baraldi
Pier Giovanni
PG
Dipartimento di Scienze Farmaceutiche and Dipartimento di Medicina Clinica e Sperimentale-Sezione di Farmacologia, Università di Ferrara, 44100 Ferrara, Italy. pgb@dns.unife.it
Fruttarolo
Francesca
F
Tabrizi
Mojgan Aghazadeh
MA
Preti
Delia
D
Romagnoli
Romeo
R
El-Kashef
Hussein
H
Moorman
Allan
A
Varani
Katia
K
Gessi
Stefania
S
Merighi
Stefania
S
Borea
Pier Andrea
PA
D000818:Animals; D001667:Binding, Competitive; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D012995:Solubility; D013329:Structure-Activity Relationship
D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3