3584-65-4Relevant articles and documents
Design, synthesis and biological evaluation of novel scaffold benzo[4,5]imidazo [1,2-a]pyrazin-1-amine: Towards adenosine A2A receptor (A2A AR) antagonist
Reddy, G. Lakshma,Sarma, Rupam,Liu, Shuhao,Huang, Weifeng,Lei, Jinping,Fu, Jiasheng,Hu, Wenhao
, (2020/12/17)
Antagonists of adenosine receptor are under exploration as potential drug candidates for treatment of neurological disorders, depression, certain cancers and potentially used as a cancer immunotherapy. Herein, we describe design and synthesis of novel scaffold benzo[4,5]imidazo [1,2-a]pyrazin-1-amine (6) derivatives. All the compounds were evaluated for A2A AR antagonist activity and displayed encouraging results (IC50 9–300 nM) of A2A AR antagonist binding affinity in biochemical assay. Compound 27 exhibits good activity in A2A AR antagonist cAMP functional assay (IC50 31 nM) and further this compound shows T-cell activation at the IL-2 production assay (EC50 165 nM). Molecular docking studies were carried out to rationalize the observed binding affinity of compound 27.
Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor-2 Positive Allosteric Modulators against Migraine
Szabó, Gy?rgy,Erdélyi, Péter,Kolok, Sándor,Vastag, Mónika,Halász, Attila S.,Kis-Varga, Istvánné,Lévay, Gy?rgy I.,Béni, Zoltán,Kóti, János,Greiner, István,Keser?, Gy?rgy M.
, p. 8607 - 8620 (2021/06/28)
Our previous scaffold-hopping attempts resulted in dihydropyrazino-benzimidazoles as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs) with suboptimal drug-like profiles. Here, we report an alternative fragment-based optimization strategy applied on the new dihydropyrazino-benzimidazolone scaffold. Analyzing published high-affinity mGluR2 PAMs, we used a pharmacophore-guided approach to identify suitable growing vectors and optimize the scaffold in these directions. This strategy resulted in a new fragment like lead (34) with improved druglike properties that were translated to sufficient pharmacokinetics and validated proof-of-concept studies in migraine. Gratifyingly, compound34showed reasonable activity in the partial infraorbital nerve ligation, a migraine disease model that might open this indication for mGluR2 PAMs.
Reversing binding sensitivity to A147T translocator protein
Banister, Samuel D.,Freelander, Isaac,Ittner, Lars M.,Kassiou, Michael,Reekie, Tristan A.,Vo, Sophie V.,Werry, Eryn L.
, p. 511 - 517 (2020/05/13)
The translocator protein (TSPO) is a target for the development of neuroinflammation imaging agents. Clinical translation of TSPO PET ligands, such as [11C]DPA-713, has been hampered by the presence of a common polymorphism (A147T TSPO), at which all second-generation TSPO ligands lose affinity. Little is known about what drives binding at A147T compared to WT TSPO. This study aimed to identify moieties in DPA-713, and related derivatives, that influence binding at A147T compared to WT TSPO. We found changes to the nitrogen position and number in the heterocyclic core influences affinity to WT and A147T to a similar degree. Hydrogen bonding groups in molecules with an indole core improve binding at A147T compared to WT, a strategy that generated compounds that possess up to ten-times greater affinity for A147T. These results should inform the future design of compounds that bind both A147T and WT TSPO for use in neuroinflammation imaging.
