BIM-46174 fragments as potential ligands of G proteins

Jim Küppers; Tobias Benkel; Suvi Annala; Gregor Schnakenburg; Evi Kostenis; Michael Gütschow

doi:10.1039/c9md00269c

BIM-46174 fragments as potential ligands of G proteins

Medchemcomm. 2019 Aug 21;10(10):1838-1843. doi: 10.1039/c9md00269c. eCollection 2019 Oct 1.

Authors

Jim Küppers¹, Tobias Benkel^{2

3}, Suvi Annala², Gregor Schnakenburg⁴, Evi Kostenis², Michael Gütschow¹

Affiliations

¹ Pharmaceutical Institute , Pharmaceutical Chemistry I , University of Bonn , An der Immenburg 4 , 53121 Bonn , Germany . Email: [email protected].
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 , Bonn , Germany.
⁴ Institute of Inorganic Chemistry , University of Bonn , Gerhard-Domagk-Str. 1 , 53121 Bonn , Germany.

Abstract

The 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine derivative BIM-46174 has received attention as Gα_q inhibitor. We conducted structural reductions to monocyclic and bicyclic substructures to explore the chemical space of BIM fragments and to gain insights into the pharmacophore of BIM-type Gα_q inhibitors. Two piperazin-2-one-containing fragments and a small library of bicyclic lactams featuring fused pyrazine and diazepine rings were synthesized and evaluated. The results of a second messenger-based cellular assay indicate that the entire BIM structure is required for efficient Gα_q inhibition.