Results
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