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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