| Autor: |
Hulshof, J. W., Casarosa, P., Menge, W. M. P. B., Kuusisto, L. M. S., Goot, H. van der, Smit, M. J., Esch, I. J. P. de, Leurs, R. |
| Zdroj: |
Journal of Medicinal Chemistry; October 2005, Vol. 48 Issue: 20 p6461-6471, 11p |
| Abstrakt: |
US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signals in 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 agonist for a viral-encoded chemokine receptor. Interestingly, this compound is able to partially inhibit the viral entry of HIV-1. In this study we describe the synthesis of 1 and several of its analogues and unique structure−activity relationships for this first class of small-molecule ligands for the chemokine receptor US28. Moreover, the compounds have been pharmacologically characterized as inverse agonists on US28. By modification of lead structure 1, it is shown that a 4-phenylpiperidine moiety is essential for affinity and activity. Other structural features of 1 are shown to be of less importance. These compounds define the first SAR of ligands on a viral GPCR (US28) and may therefore serve as important tools to investigate the significance of US28-mediated constitutive activity during viral infection. |
| Databáze: |
Supplemental Index |
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