A new series of pyrazolotriazolopyrimidines bearing different substitutions on the phenylcarbamoyl moieties at the N5 position, being highly potent and selective human A3 adenosine receptor antagonists, is described. The compds. represent an extension and an improvement of our previous work on this class of compds. (J. Med. Chem. 1999, 42, 4473-4478; J. Med. Chem. 2000, 43, 4768-4780). All the synthesized compds. showed A3 adenosine receptor affinity in the subnanomolar range and high levels of selectivity in radioligand binding assays at the human A1, A2A, A2B, and A3 adenosine receptors. In particular, the effect of the substitution and its position on the Ph ring have been studied. From binding data, it is evident that the unsubstituted derivs. on the Ph ring (e.g., compd. 59, hA3 = 0.16 nM, hA1/hA3 = 3713, hA2A/hA3 = 2381, hA2B/hA3 = 1388) showed the best profile in terms of affinity and selectivity at the human A3 adenosine receptors. The introduction of a sulfonic acid moiety at the para position on the Ph ring was attempted in order to design water sol. derivs. However, this substitution led to a dramatic decrease of affinity at all four adenosine receptor subtypes. A computer-generated model of the human A3 receptor was built and analyzed to better interpret these results, demonstrating that steric control, in particular at the para position on the Ph ring, plays a fundamental role in the receptor interaction. Some of the synthesized compds. 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 with IC50 values in the nanomolar range, with a statistically significative linear relationship with the binding data.
Synthesis, biological activity, and molecular modeling investigation of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as human A(3) adenosine receptor antagonists
BARALDI, Pier Giovanni;CACCIARI, Barbara;VARANI, Katia;GESSI, Stefania;BOREA, Pier Andrea
2002
Abstract
A new series of pyrazolotriazolopyrimidines bearing different substitutions on the phenylcarbamoyl moieties at the N5 position, being highly potent and selective human A3 adenosine receptor antagonists, is described. The compds. represent an extension and an improvement of our previous work on this class of compds. (J. Med. Chem. 1999, 42, 4473-4478; J. Med. Chem. 2000, 43, 4768-4780). All the synthesized compds. showed A3 adenosine receptor affinity in the subnanomolar range and high levels of selectivity in radioligand binding assays at the human A1, A2A, A2B, and A3 adenosine receptors. In particular, the effect of the substitution and its position on the Ph ring have been studied. From binding data, it is evident that the unsubstituted derivs. on the Ph ring (e.g., compd. 59, hA3 = 0.16 nM, hA1/hA3 = 3713, hA2A/hA3 = 2381, hA2B/hA3 = 1388) showed the best profile in terms of affinity and selectivity at the human A3 adenosine receptors. The introduction of a sulfonic acid moiety at the para position on the Ph ring was attempted in order to design water sol. derivs. However, this substitution led to a dramatic decrease of affinity at all four adenosine receptor subtypes. A computer-generated model of the human A3 receptor was built and analyzed to better interpret these results, demonstrating that steric control, in particular at the para position on the Ph ring, plays a fundamental role in the receptor interaction. Some of the synthesized compds. 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 with IC50 values in the nanomolar range, with a statistically significative linear relationship with the binding data.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
