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.
- 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.
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.
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Cat. No.Product NameDescriptionTargetResearch Area
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target: Neurotensin Receptor; MMP; EGFR; Toll-like Receptor (TLR); Wnt; Caspase; PARP; MyD88; NF-κB; TNF Receptor; Apoptosis