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GABAA 受体亚型选择性调节剂。I. α2/α3 选择性激动剂作为非镇静性抗焦虑药。

GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics.

机构信息

Department of Neuroscience, Janssen Pharmaceutical Research and Development, Beerse, Belgium.

出版信息

Curr Top Med Chem. 2011;11(9):1176-202. doi: 10.2174/156802611795371350.

Abstract

The prototypic benzodiazepines, such as diazepam, are not only anxiolytic but also produce sedation. These effects are mediated by GABA(A) receptors containing either an α1, α2, α3 or α5 subunit at which the positive modulatory effects (i.e., agonist efficacy) of benzodiazepines are mediated via a specific benzodiazepine recognition site. Recent molecular genetic and pharmacological data point to α1-containing GABA(A) receptors as the "sedative" and α2- and/or α3-containing receptors as the "anxiolytic" subtype(s). Therefore, at Merck Sharp & Dohme attempts were made to identify subtype-selective compounds that modulate α2/α3 but not α1 receptor function with the prediction that such compounds would be non-sedating anxiolytics. The initial strategy for discovering such "anxioselective" compounds focussed on producing compounds with much higher affinity at the α2/α3 compared to α1 subtypes. The starting point for this approach was the triazolophthalazine series developed from a combination of a screening hit and a literature compound [1]. However, the maximum α3 versus α1 binding selectivity that could be achieved in this series was 12-fold and this was not considered sufficient for an appropriate in vivo pharmacological differentiation compared to non-selective compounds. Nevertheless, within this series compounds demonstrating (albeit to a limited extent) higher agonist efficacy at the α3 versus α1 subtype were also identified. This suggested that it might be possible to synthesize a compound with higher efficacy at the α2 and/or α3 compared to α1 subtypes, ideally with no efficacy at the latter subtype (i.e., a compound with subtype-selective efficacy). By changing the structure from a triazolophthalazine to a triazolopyridazine core, a number of either pharmacological tool compounds (L-838417, MRK-067 and MRK-696) or clinical development candidates (MRK-409 and TPA023) were identified. Encouraged by the success of this approach and the observation that the benzimidazole NS-2710 had a modest degree of α3 versus α1 selectivity efficacy, a structurally-related class of imidazopyridines was also explored. The introduction of an additional nitrogen into the imidazopyridine core gave the imidazopyrimidine series which initially had issues with poor dog pharmacokinetics. However, this was resolved and resulted in the identification of the development candidates MRK-623 and MRK-898. A fluoroimidazopyridine was found to be a bioisostere of the imidazopyrimidine core and in this series the α3-selective tool compound TP003 was identified. The addition of a further nitrogen into the imidazopyrimidine core produced the imidazotriazine series, which yielded the clinical candidate TPA023B. Imidazopyrazinone and imidazotriazinone compounds offered no advantages over their respective imidazopyrimidine and imidazotriazine analogues. Additional pharmacological tool compounds were identified within the pyridine, pyrazolotriazine, pyridazine and pyrazolopyridone series highlighting the general feasibility of GABA(A) receptor subtype selective efficacy as a strategy for developing compounds with novel in vitro and in vivo profiles.

摘要

原型苯二氮䓬类药物,如地西泮,不仅具有抗焦虑作用,还具有镇静作用。这些作用是通过包含 α1、α2、α3 或 α5 亚基的 GABA(A) 受体介导的,其中苯二氮䓬类药物的正变构调节效应(即激动剂效力)通过特定的苯二氮䓬识别位点介导。最近的分子遗传和药理学数据表明,α1 包含的 GABA(A) 受体是“镇静”亚型,α2 和/或 α3 包含的受体是“抗焦虑”亚型。因此,在默克夏普 & 多姆公司,人们试图识别出能够调节 α2/α3 但不调节 α1 受体功能的亚型选择性化合物,预测此类化合物将是非镇静性抗焦虑药。发现这种“焦虑选择性”化合物的初始策略集中在产生与 α1 亚型相比在 α2/α3 上具有更高亲和力的化合物。这种方法的起点是从筛选命中和文献化合物组合开发的三唑并酞嗪系列[1]。然而,在该系列中可以实现的最大 α3 与 α1 结合选择性为 12 倍,与非选择性化合物相比,这被认为不足以进行适当的体内药理学区分。尽管如此,在该系列中,还鉴定出了在 α3 与 α1 亚型上具有更高激动剂效力(尽管程度有限)的化合物。这表明,有可能合成一种在 α2 和/或 α3 上比 α1 亚型具有更高效力的化合物,理想情况下在后者亚型上没有效力(即具有亚型选择性效力的化合物)。通过将结构从三唑并酞嗪改为三唑并吡啶核,发现了一些药理学工具化合物(L-838417、MRK-067 和 MRK-696)或临床开发候选药物(MRK-409 和 TPA023)。这种方法的成功以及观察到苯并咪唑 NS-2710 具有一定程度的 α3 与 α1 选择性效力的结果,促使人们探索了一类结构相关的咪唑并吡啶类化合物。在咪唑并吡啶核中引入额外的氮原子得到了咪唑并嘧啶系列,该系列最初存在狗药代动力学不佳的问题。然而,这一问题得到了解决,并导致了开发候选药物 MRK-623 和 MRK-898 的鉴定。发现氟咪唑并吡啶是咪唑并嘧啶核的生物等排体,在该系列中,鉴定出了具有 α3 选择性的工具化合物 TP003。在咪唑并嘧啶核中进一步引入一个氮原子得到了咪唑并三嗪系列,得到了临床候选药物 TPA023B。咪唑并吡嗪酮和咪唑并三嗪酮化合物与各自的咪唑并嘧啶和咪唑并三嗪类似物相比没有优势。在吡啶、吡唑并三嗪、哒嗪和吡唑并吡啶酮系列中发现了其他药理学工具化合物,突出了 GABA(A) 受体亚型选择性效力作为开发具有新型体外和体内特征的化合物的策略的一般可行性。

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