Abstract
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.
Original language | English |
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Pages (from-to) | 6461-71 |
Number of pages | 11 |
Journal | Journal of Medicinal Chemistry |
Volume | 48 |
Issue number | 20 |
DOIs | |
Publication status | Published - 6 Oct 2005 |
Keywords
- Animals
- Antiviral Agents
- Benzhydryl Compounds
- COS Cells
- Cercopithecus aethiops
- Cytomegalovirus
- Humans
- Inositol Phosphates
- Ligands
- Piperidines
- Radioligand Assay
- Receptors, Chemokine
- Structure-Activity Relationship
- Viral Proteins
- Journal Article
- Research Support, Non-U.S. Gov't