174648-60-3

Upstream product

• 3326-71-4 2-furoic acid hydrazide 
• 122-51-0 orthoformic acid triethyl ester 
• 16617-46-2 3-amino-4-cyano-2H-pyrazole 
• 174648-50-1 5-amino-4-cyano-1-(3-phenylpropyl)pyrazole 
• 948552-92-9 Furan-2-carboxylic acid [4-imino-1-(3-phenyl-propyl)-1,4-dihydro-pyrazolo[3,4-d]pyrimidin-5-yl]-amide 

Downstream Products

• 174648-69-2 5-amino-1-(3-phenylpropyl)-4-<3-(2-furyl)-1,2,4-triazol-5-yl>pyrazole 
• 174648-45-4 Sch 63390 

Relevant academic research and scientific papers

Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A3 adenosine receptor antagonists: Influence of the chain at the N8 pyrazole nitrogen

An enlarged series of pyrazolotriazolopyrimidines previously reported, in preliminary form (Baraldi et al. J. Med. Chem. 1999, 42, 4473-4478), as highly potent and selective human A3 adenosine receptor antagonists is described. The synthesized compounds showed A3 adenosine receptor affinity in the sub-nanomolar range and high levels of selectivity evaluated in radioligand binding assays at human A1, A(2A), A(2B), and A3 adenosine receptors. In particular, the effect of the chain at the N8 pyrazole nitrogen was analyzed. This study allowed us to identify the derivative with the methyl group at the N8 pyrazole combined with the 4-methoxyphenylcarbamoyl moiety at the N5 position as the compound with the best binding profile in terms of both affinity and selectivity (hA3 = 0.2 nM, hA1/hA3 = 5485, hA2A/hA3 = 6950, hA(2B)/hA3 = 1305). All the compounds proved to be full antagonists in a specific functional model where the inhibition of cAMP generation by IB-MECA was measured in membranes of CHO cells stably transfected with the human A3 receptor. The new compounds are among the most potent and selective A3 antagonists so far described. The derivatives with higher affinity at human A3 adenosine receptors proved to be antagonists, in the cAMP assay, capable of inhibiting the effect of IB-MECA with IC50 values in the nanomolar range, with a trend strictly similar to that observed in the binding assay. Also a molecular modeling study was carried out, with the aim to identify possible pharmacophore maps. In fact, a sterically controlled structure-activity relationship was found for the N8 pyrazole substituted derivatives, showing a correlation between the calculated molecular volume of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives and their experimental K(i) values.

Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives: Potent and selective A2A adenosine antagonists

A series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives (10a-o,q,r), bearing alkyl and aralkyl chains on positions 7 and 8, were synthesized in the attempt to obtain potent and selective antagonists for the A2A adenosine receptor subtype. The compounds were tested in binding and functional assays to evaluate their potency for the A2A compared with the A1 adenosine receptor subtype. In binding studies in rat brain membranes, most of the compounds showed affinity for A2A receptors in the low nanomolar range with a different degree of A2A versus A1 selectivity. Comparison of N7 (10a-d,h-o)- and N8 (10e-g)-substituted pyrazolo derivatives indicates that N7 substitution decreases the A1 affinity with the concomitant increase of A2A selectivity. Specifically, the introduction of a 3-phenylpropyl group at pyrazolo nitrogen in position 7 (101) increased significantly the A2A selectivity, being 210-fold, while the A2A receptor affinity remained high (Ki = 2.4 nM). With regards to the affinity for A2A receptors, also the compound 10n, bearing in the 7-position a β-morpholin-4-ylethyl group, deserves attention (K1 = 5.6 nM) even though the A2A selectivity (84-fold) was not as high as that of 101. Conversely, the compound 10m (N7-4-phenylbutyl derivative) showed a remarkable selectivity (A1/A2A ratio = 129) associated with lower A2A affinity (K1 = 21 nM). In functional studies, most of the compounds examined reversed 5′-(N-ethylcarbamoyl)adenosine-induced inhibition of rabbit platelet aggregation inhibition which is a biological response mediated by the A2A receptor subtype. The compounds are potent and selective A2A antagonists which can be useful to elucidate the pathophysiological role of this adenosine receptor subtype. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.