Total synthesis of two novel subpicomolar sarco/endoplasmatic reticulum Ca2+-ATPase inhibitors designed by an analysis of the binding site of thapsigargin

Helmer Søhoel, Tommy Liljefors, Steven V. Ley, Steven F. Oliver, Alessandra Antonello, Martin D. Smith, Carl Erik Olsen, John T. Isaacs, S. Brøgger Christensen

Research output: Contribution to journalArticlepeer-review

Abstract

Analysis of molecular interaction fields based on the published crystal structure of thapsigargin bound to the sarco/endoplasmatic reticulum Ca 2+-ATPase and analysis of the volume and shape of the ligand binding site and of the SERCA-thapsigargin interactions have enabled design of two new compounds inhibiting SERCA in the subpicomolar range. The two inhibitors were synthesized using (S)-carvone as starting material and found to be 3 and 10 times more potent than thapsigargin.

Original languageEnglish (US)
Pages (from-to)7005-7011
Number of pages7
JournalJournal of medicinal chemistry
Volume48
Issue number22
DOIs
StatePublished - Nov 3 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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