Design and Synthesis of γ- and δ-Lactarn M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity
Design and Synthesis of γ- and δ-Lactarn M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity
复制标题
DOI：
10.1021/acs.jmedchem.7b00597
复制
发表时间：
2017-08-10
影响因子：
7.3
通讯作者：
Webb, Damien
中科院分区：
文献类型：
--
作者：
Davoren, Jennifer E.;Garney, Michelle;Webb, Damien
最近的数据表明，通过亚型选择性正变构调节剂（PAM）激活毒蕈碱M 1受体有助于先前归因于M-2和M-3激活的胃肠道（GI）和心血管（CV）胆碱能不良事件（AE）。这些研究使用也表现出变构激动剂活性的PAM进行，留下了通过变构激动作用而不是变构调节的直接激活可能是不良反应的原因的可能性。本文介绍了解决这一假设的内酰胺衍生的M-1 PAM的设计和合成。该系列的先导分子化合物1（PF-06827443）是一种强效、低清除率、口服生物利用度和CNS渗透剂M-1选择性PAM，具有极低的激动剂活性。化合物1在大鼠和狗的剂量递增研究中进行了测试，发现其在与具有更多激动剂活性的先前化合物类似的治疗指数下诱导胆碱能AE和惊厥。这些结果提供了初步证据，表明M-1的正变构调节足以引起胆碱能AE。
Recent data demonstrated that activation of the muscarinic M, receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M-2 and M-3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M-1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M-1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M-1 is sufficient to elicit cholinergic AEs.