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- Title
Tetrahydroimidazo[1,2‐a]pyrazine Derivatives: Synthesis and Evaluation as Gα<sub>q</sub>‐Protein Ligands.
- Authors
Küppers, Jim; Benkel, Tobias; Annala, Suvi; Kimura, Kenichi; Reinelt, Lisa; Fleischmann, Bernd K.; Kostenis, Evi; Gütschow, Michael
- 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.
- Subjects
MOIETIES (Chemistry); STRUCTURE-activity relationships; AMINO group; LIGANDS (Chemistry); STRUCTURAL dynamics
- Publication
Chemistry - A European Journal, 2020, Vol 26, Issue 55, p12615
- ISSN
0947-6539
- Publication type
Academic Journal
- DOI
10.1002/chem.202001446