2-(4-Fluorophenyl)-1H-benzo[d]imidazole as a Promising Template for the Development of Metabolically Robust, α1β2γ2GABA-A Receptor-Positive Allosteric Modulators,ACS Chemical Neuroscience

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2-(4-Fluorophenyl)-1H-benzo[d]imidazole as a Promising Template for the Development of Metabolically Robust, α1β2γ2GABA-A Receptor-Positive Allosteric Modulators
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2023-02-27 , DOI: 10.1021/acschemneuro.2c00800
Monika Marcinkowska ₁ , Nikola Fajkis-Zajączkowska ₁ , Katarzyna Szafrańska ₁ , Jakub Jończyk ₁ , Agata Siwek ₂ , Barbara Mordyl ₂ , Tadeusz Karcz ₃ , Gniewomir Latacz ₃ , Marcin Kolaczkowski ₁

Affiliation

Modulation of α1β2γ2GABA-A receptor subpopulation expressed in the basal ganglia region is a conceptually novel mode of pharmacological strategy that offers prospects to tackle a variety of neurological dysfunction. Although clinical findings provided compelling evidence for the validity of this strategy, the current chemical space of molecules able to modulate the α1/γ2 interface of the GABA-A receptor is limited to imidazo[1,2-a]pyridine derivatives that undergo rapid biotransformation. In response to a deficiency in the chemical repertoire of GABA-A receptors, we identified a series of 2-(4-fluorophenyl)-1H-benzo[d]imidazoles as positive allosteric modulators (PAMs) with improved metabolic stability and reduced potential for hepatotoxicity, where lead molecules 9 and 23 displayed interesting features in a preliminary investigation. We further disclose that the identified scaffold shows a preference for interaction with the α1/γ2 interface of the GABA-A receptor, delivering several PAMs of the GABA-A receptor. The present work provides useful chemical templates to further explore the therapeutic potential of GABA-A receptor ligands and enriches the chemical space of molecules suitable for the interaction with the α1/γ2 interface.

中文翻译：

2-(4-氟苯基)-1H-苯并[d]咪唑作为开发代谢稳健的 α1β2γ2GABA-A 受体正变构调节剂的有前途的模板

调节在基底神经节区域表达的 α1β2γ2GABA-A 受体亚群是一种概念上新颖的药理学策略模式，为解决各种神经功能障碍提供了前景。尽管临床研究结果为该策略的有效性提供了令人信服的证据，但目前能够调节 GABA-A 受体 α1/γ2 界面的分子的化学空间仅限于经历快速生物转化的咪唑并 [1,2-a]吡啶衍生物. 为了应对 GABA-A 受体化学库的缺陷，我们鉴定了一系列 2-(4-氟苯基)-1 H -苯并[ d]咪唑作为正变构调节剂 (PAM)，具有改善的代谢稳定性和降低的肝毒性可能性，其中先导分子9和23在初步研究中显示出有趣的特征。我们进一步披露，已识别的支架显示出与 GABA-A 受体的 α1/γ2 界面相互作用的偏好，提供 GABA-A 受体的几种 PAM。目前的工作提供了有用的化学模板，以进一步探索 GABA-A 受体配体的治疗潜力，并丰富了适合与 α1/γ2 界面相互作用的分子的化学空间。

更新日期：2023-02-27

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