Combinatorial Chemistry Unit (COMBIOMED), Institute of Industrial Pharmacy, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
J Med Chem. 2011 Jan 27;54(2):457-71. doi: 10.1021/jm100843z. Epub 2010 Dec 27.
Two regioisomeric series of diaryl 2- or 4-amidopyrimidines have been synthesized and their adenosine receptor affinities were determined in radioligand binding assays at the four human adenosine receptors (hARs). Some of the ligands prepared herein exhibit remarkable affinities (K(i) < 10 nm) and, most noticeably, the absence of activity at the A(1), A(2A), and A(2B) receptors. The structural determinants that support the affinity and selectivity profiles of the series were highlighted through an integrated computational approach, combining a 3D-QSAR model built on the second generation of GRid INdependent Descriptors (GRIND2) with a novel homology model of the hA(3) receptor. The robustness of the computational model was subsequently evaluated by the design of new derivatives exploring the alkyl substituent of the exocyclic amide group. The synthesis and evaluation of the novel compounds validated the predictive power of the model, exhibiting excellent agreement between predicted and experimental activities.
已经合成了两个区域异构体系列的二芳基 2-或 4-酰胺嘧啶，并在放射性配体结合测定法中在四个人类腺苷受体（hARs）上测定了它们的腺苷受体亲和力。本文制备的一些配体表现出显著的亲和力（Ki < 10 nM），最值得注意的是，它们在 A1、A2A 和 A2B 受体上没有活性。通过结合第二代 GRid INdependent Descriptors（GRIND2）构建的 3D-QSAR 模型和新型 hA3 受体同源模型，突出了支持该系列亲和力和选择性特征的结构决定因素。通过设计探索外环酰胺基团的烷基取代基的新衍生物来评估计算模型的稳健性。新型化合物的合成和评估验证了该模型的预测能力，显示出预测活性与实验活性之间的极好一致性。
