Several classes of heterocyclic derivatives have been reported as AR antagonists with high levels of both affinity and selectivity. In particular, in recent years we investigated in depth the nucleus of triazolo-pyrazolo-pyrimidine as a basis for designing ARs antagonists. Nevertheless, this class of compounds, like other tricyclic structures, was subject to poor water solubility and more importantly complicated synthetic routes. In consideration of these problems, medicinal chemists recently focused their attention on the synthesis of more simplified heterocyclic derivatives, in particular bicyclic systems. The 1,2,4-triazolo[1,5-c]pyrimidines possesses a low molecular weight and less nitrogen atoms than pyrazolo-triazolo-pyrimidines, thus it may be a scaffold with promising pharmacokinetics properties. A preliminary investigation on these molecules was carried out introducing arylacetyl or arylcarbamoyl moieties at the N5 position, which enhanced affinity at the hA2B and hA3 ARs, when utilized on the pyrazolo-triazolo-pyrimidine nucleus. In addition, in order to better investigate the possible substitutions on this scaffold, also moieties without a carbonyl group (alkyl and aryl moieties) were introduced at N5 position. Surprisingly, compound bearing the methylamino substitution at the 5 position displays high affinity (KihA3=4.14 nM) and selectivity (236, 25, 592-fold vs hA1, hA2A and hA2B ARs) at the hA3AR subtype . The analogue was docked in a homology model of the hA3AR based on the crystallographic structure of the hA2AAR, confirming the interactions with residues important to have potency at the hA3AR.
References
[1]Moro, S., et al. Med. Res. Rev. 2006, 26 (2), 131-159.
[2]Cacciari, B., et al. Purinergic Signalling 2007, 3, 183-193.
