Davoren Jennifer E, Garnsey Michelle, Pettersen Betty, Brodney Michael A, Edgerton Jeremy R, Fortin Jean-Philippe, Grimwood Sarah, Harris Anthony R, Jenkinson Stephen, Kenakin Terry, Lazzaro John T, Lee Che-Wah, Lotarski Susan M, Nottebaum Lisa, O'Neil Steven V, Popiolek Michael, Ramsey Simeon, Steyn Stefanus J, Thorn Catherine A, Zhang Lei, Webb Damien
Drug Safety Research and Development, Pfizer Worldwide Research and Development , La Jolla, California 92121, United States.
Department of Pharmacology, University of North Carolina School of Medicine , Chapel Hill, North Carolina 27599, United States.
J Med Chem. 2017 Aug 10;60(15):6649-6663. doi: 10.1021/acs.jmedchem.7b00597. Epub 2017 Jul 26.
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 and M 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 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-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 is sufficient to elicit cholinergic AEs.
近期数据表明，一种亚型选择性正变构调节剂（PAM）激活毒蕈碱M受体，会导致先前归因于M和M激活的胃肠道（GI）和心血管（CV）胆碱能不良事件（AE）。这些研究使用的PAM也表现出变构激动剂活性，这使得变构激动作用而非变构调节直接激活可能是不良反应的原因这一可能性仍然存在。本文描述了用于验证该假设的内酰胺衍生的M PAM的设计与合成。该系列的先导分子化合物1（PF-06827443）是一种强效、低清除率、口服生物可利用且可穿透中枢神经系统的M选择性PAM，激动剂活性极小。化合物1在大鼠和犬的剂量递增研究中进行了测试，结果发现，与先前具有更强激动剂活性的化合物相比，它在相似的治疗指数下会诱发胆碱能AE和惊厥。这些发现提供了初步证据，证明M的正变构调节足以引发胆碱能AE。
