| Abstract
| - US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signalsin a constitutively active manner. Recently, we identified 1 {5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylpentanenitrile} as the first reported nonpeptidergic inverse agonistfor a viral-encoded chemokine receptor. Interestingly, this compound is able to partially inhibitthe viral entry of HIV-1. In this study we describe the synthesis of 1 and several of its analoguesand unique structure−activity relationships for this first class of small-molecule ligands forthe chemokine receptor US28. Moreover, the compounds have been pharmacologicallycharacterized as inverse agonists on US28. By modification of lead structure 1, it is shownthat a 4-phenylpiperidine moiety is essential for affinity and activity. Other structural featuresof 1 are shown to be of less importance. These compounds define the first SAR of ligands on aviral GPCR (US28) and may therefore serve as important tools to investigate the significanceof US28-mediated constitutive activity during viral infection.
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