Pyrrolo- and pyrazolo-[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as adenosine receptor antagonists.
The discovery and development of adenosine receptor antagonists have represented for years an attractive field of research from the perspective of identifying new drugs for the treatment of widespread disorders such as inflammation, asthma and Parkinson's disease. The present work can be considered as an extension of our structure-activity relationship studies on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) nucleus, extensively investigated by us as a useful template, in particular, for the identification of A(2A) and A(3) adenosine receptor antagonists. In order to explore the role of the nitrogen at the 7-position, we performed a new synthetic strategy for the preparation of pyrrolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives which can be considered as 7-deaza analogues of the parent PTPs. We also synthesised a novel series of pyrazolo[3,4-e][1,2,4]triazolo[1,5-c]pyrimidines as junction isomers of the reference compounds. In both cases we obtained some examples of potent antagonists (K(i) in the low nanomolar range) with variable selectivity profiles in relation to the nature of substituents introduced at the C(5)-, N(8)- and/or N(9)-positions. The pyrrolo-triazolo-pyrimidine derivative 9b appeared to be a potent A(3) adenosine receptor antagonist (K(i)=10 nM) with good selectivity over hA(1) (74-fold) and hA(2A) (20-fold) adenosine receptors combined with low activity at the hA(2B) subtype (IC(50)=906 nM). Moreover, some examples of high-affinity A(1)/A(2A) dual antagonists have been identified in both series. This work constitutes a new and important contribution for the comprehension of the interaction between PTPs and adenosine receptors.
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy. baraldi@dns.unife.it
Pier Giovanni
PG
Baraldi
Giulia
G
Saponaro
Mojgan
M
Aghazadeh Tabrizi
Stefania
S
Baraldi
Romeo
R
Romagnoli
Allan R
AR
Moorman
Katia
K
Varani
Pier Andrea
PA
Borea
Delia
D
Preti
D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D058915:Purinergic P1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D014230:Triazoles; C045575:1,2,4-triazole; C030986:pyrimidine