Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28

Janneke W Hulshof, Paola Casarosa, Wiro M P B Menge, Leena M S Kuusisto, Henk van der Goot, Martine J Smit, Iwan J P de Esch, Rob Leurs

    Research output: Contribution to JournalArticleAcademicpeer-review

    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 languageEnglish
    Pages (from-to)6461-71
    Number of pages11
    JournalJournal of Medicinal Chemistry
    Volume48
    Issue number20
    DOIs
    Publication statusPublished - 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

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