2. Academic Validation
  3. Tetrahydroimidazo[1,2-a]pyrazine Derivatives: Synthesis and Evaluation as Gαq -Protein Ligands

Tetrahydroimidazo[1,2-a]pyrazine Derivatives: Synthesis and Evaluation as Gαq -Protein Ligands

  • Chemistry. 2020 Oct 1;26(55):12615-12623. doi: 10.1002/chem.202001446.
Jim Küppers 1,  Tobias Benkel 2 3,  Suvi Annala 2,  Kenichi Kimura 4,  Lisa Reinelt 1,  Bernd K Fleischmann 4,  Evi Kostenis 2,  Michael Gütschow 1
Affiliations

Affiliations

  • 1 Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
  • 2 Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115, Bonn, Germany.
  • 3 Research Training Group 1873, University of Bonn, 53115, Bonn, Germany.
  • 4 Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
PMID: 32428383 DOI: 10.1002/chem.202001446
Abstract

The 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine derivative BIM-46174 and its dimeric form BIM-46187 (1) are heterocyclized dipeptides that belong to the very few cell-permeable compounds known to preferentially silence Gαq proteins. To explore the chemical space of Gαq inhibitors of the Bim chemotype, a combinatorial approach was conducted towards a library of Bim molecules. This library was evaluated in a second messenger-based fluorescence assay to analyze the activity of Gαq proteins through the determination of intracellular myo-inositol 1-phosphate. Structure-activity relationships were deduced and structural requirements for biological activity obtained, which were (i) a redox reactive thiol/disulfane substructure, (ii) an N-terminal basic amino group, (iii) a cyclohexylalanine moiety, and (iv) a bicyclic skeleton. Active compounds exhibited cellular toxicity, which was investigated in detail for the prototypical inhibitor 1. This compound affects the structural cytoskeletal dynamics in a Gαq/11 -independent manner.

Keywords

Davidson cyclization; G proteins; lactamization; structure-activity relationships; toxicity.

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