2,4,6-trisubstituted pyrimidines as a new class of selective adenosine A1 receptor antagonists

Adenosine receptor antagonists usually possess a bi- or tricyclic heteroaromatic structure at their core with varying substitution patterns to achieve selectivity and/or greater affinity. Taking into account molecular modeling results from a series of potent adenosine A(1) receptor antagonists, a pharmacophore was derived from which we show that a monocyclic core can be equally effective. To achieve a compound that may act at the GNS we propose imposing a restriction related to its polar surface area (PSA). In consequence, we have synthesized two novel series of pyrimidines, possessing good potency at the adenosine A, receptor and desirable PSA values. In particular, compound 30 (LUF 5735) displays excellent A, affinity (K-i = 4 nM) and selectivity (less than or equal to50% displacement of 1 muM concentrations of the radioligand at the other three adenosine receptors) and has a PSA value of 53 Angstrom2.