N8-Isopentyl and N8-Phenylethyl Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine Derivatives as Adenosine Receptor Antagonists

Adenosine is a neuromodulator exerting several functions through the activation of specific G protein-coupled receptors that are classified into four different subtypes, termed A1, A2A, A2B and A3 adenosine receptors (AR). Diverse potent and selective ligands for each subtype have demonstrated the potential therapeutic role of the adenosine receptors in several physiopathological processes. In particular, A1AR selective antagonists have been reported as promising candidates for the treatment of cognitive disorders, such as dementia. The antagonism selectivity for A1AR is also the proposed mechanism for some diuretic agents, which are considered effective in congestive heart failure and in edema. A2AAR antagonists have a neuroprotective activity during ischemic processes and seem to play a role in the reduction of neuronal damage in Parkinson’s and Huntington’s diseases. A potential therapeutic activity in the asthma has been discovered for A2BAR selective antagonists. A2BAR antagonists are also studied as hypoglycemic agents in diabetes, while A3AR antagonists have a potential application in the treatment of glaucoma. In this research field, our group has reported a large series of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) derivatives as highly potent and selective hA3AR antagonists. In particular, we observed that the simultaneous introduction of a methyl group at the N8 position and the presence of aryl carbamoyl or arylacetyl moieties at the N5 position led to potent and selective hA3AR antagonists. Recently, we reported a new series of PTP where we have performed an extensive exploration of new possible substituents of different nature and size at the N5 position as new possible spacers and site of linkage for functionalizing moieties, that can be useful in the study of the physiological and physio-pathological roles of ARs. This work demonstrated that also alkyl or aralkyl amino groups at the 5 position are able to give highly potent A3AR antagonists. For this reason we decided to synthetize a new PTP series, maintaining alkyl or aralkyl amino substituents at the 5 position, while introducing an isopentyl or a phenylethyl moiety at the N8 position. The isopentyl and phenylethyl moieties were introduced to explore their effect on selectivity towards ARs and in order to open the possibility to design new pharmacological tools for the investigation of the various AR subtypes. References 1. Müller, C.E., et al., 2011. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta 1808:1290–1308. 2. Cheong, S.L., et al., 2011. Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships. Int J Med Chem. 3. Federico, S., et al., 2012. Exploring the Directionality of 5‑Substitutions in a New Series of 5‑alkylaminopyrazolo[4,3‑e]1,2,4-triazolo[1,5‑c]pyrimidine as a Strategy To Design Novel Human A3 Adenosine Receptor Antagonists. J Med Chem 55: 9654-9668.