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 A1 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 CNS 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 A1 receptor and desirable PSA values. In particular, compound 30 (LUF 5735) displays excellent A1 affinity (Ki = 4 nM) and selectivity (< or =50% displacement of 1 muM concentrations of the radioligand at the other three adenosine receptors) and has a PSA value of 53 A2.

中文翻译：

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2,4,6-三取代的嘧啶类是一类新型的选择性腺苷A1受体拮抗剂。

腺苷受体拮抗剂通常在其核心处具有双环或三环杂芳族结构，具有不同的取代模式以实现选择性和/或更大的亲和力。考虑到一系列有效的腺苷A1受体拮抗剂的分子建模结果，从药效基团衍生出来，我们证明了单环核心同样有效。为了获得可能作用于中枢神经系统的化合物，我们建议对其极性表面积（PSA）施加限制。因此，我们合成了两个新颖的嘧啶系列，它们对腺苷A1受体具有良好的效力，并具有理想的PSA值。特别是，化合物30（LUF 5735）显示出出色的A1亲和力（Ki = 4 nM）和选择性（<