期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 2, 页码 457-471出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm100843z
关键词
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资金
- Fondo Europeo de Desarrollo Social (FEDER)
- Galician Government [09CSA016234PR, PS09/63]
- Conselleria de Educacion (Xunta de Galicia)
- Instituto de Salud Carlos III (Ministerio de Ciencia e Innovacion, Spain)
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 G Rid 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.
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