Tetrahydroimidazopyrazine Derivatives: Synthesis and Evaluation as Gαq‐Protein Ligands

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,...

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Bibliographic Details
Published in:Chemistry : a European journal 2020-10, Vol.26 (55), p.12615-12623
Main Authors: Küppers, Jim, Benkel, Tobias, Annala, Suvi, Kimura, Kenichi, Reinelt, Lisa, Fleischmann, Bernd K, Kostenis, Evi, Gütschow, Michael
Format: Article
Language:English
Subjects:
Biological activity
Chemistry
Combinatorial analysis
Cytoskeleton
Fluorescence
Libraries
Proteins
Pyrazine
Substructures
Toxicity
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Summary: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.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.202001446