Küppers Jim, Benkel Tobias, Annala Suvi, Schnakenburg Gregor, Kostenis Evi, Gütschow Michael
Pharmaceutical Institute , Pharmaceutical Chemistry I , University of Bonn , An der Immenburg 4 , 53121 Bonn , Germany . Email:
Molecular, Cellular and Pharmacobiology Section , Institute for Pharmaceutical Biology , University of Bonn , Nussallee 6 , 53115 Bonn , Germany.
Medchemcomm. 2019 Aug 21;10(10):1838-1843. doi: 10.1039/c9md00269c. eCollection 2019 Oct 1.
The 5,6,7,8-tetrahydroimidazo[1,2-]pyrazine derivative BIM-46174 has received attention as Gα 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 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 inhibition.
5,6,7,8-四氢咪唑并[1,2 - ]吡嗪衍生物BIM - 46174作为Gα抑制剂受到关注。我们对单环和双环亚结构进行了结构简化，以探索BIM片段的化学空间，并深入了解BIM型Gα抑制剂的药效团。合成并评估了两个含哌嗪 - 2 - 酮的片段以及一个以稠合吡嗪和二氮杂环庚烷环为特征的双环内酰胺小文库。基于第二信使的细胞试验结果表明，有效的Gα抑制需要完整的BIM结构。
