Vanderbilt Center for Neuroscience Drug Discovery , Vanderbilt University Medical Center , Nashville , Tennessee 37232 , United States.
Department of Pharmacology , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States.
ACS Chem Neurosci. 2019 Mar 20;10(3):1035-1042. doi: 10.1021/acschemneuro.8b00311. Epub 2018 Aug 9.
This Letter describes the chemical optimization of a new series of muscarinic acetylcholine receptor subtype 1 (M) positive allosteric modulators (PAMs) based on novel tricyclic triazolo- and imidazopyridine lactam cores, devoid of M agonism, e.g., no M ago-PAM activity, in high expressing recombinant cell lines. While all the new tricyclic congeners afforded excellent rat pharmacokinetic (PK) properties (CL < 8 mL/min/kg and t > 5 h), regioisomeric triazolopyridine analogues were uniformly not CNS penetrant ( K < 0.05), despite a lack of hydrogen bond donors. However, removal of a single nitrogen atom to afford imidazopyridine derivatives proved to retain the excellent rat PK and provide high CNS penetration ( K > 2), despite inclusion of a basic nitrogen. Moreover, 24c was devoid of M agonism in high expressing recombinant cell lines and did not induce cholinergic seizures in vivo in mice. Interestingly, all of the new M PAMs across the diverse tricyclic heterocyclic cores possessed equivalent CNS MPO scores (>4.5), highlighting the value of both "medicinal chemist's eye" and experimental data, e.g., not sole reliance (or decision bias) on in silico calculated properties, for parameters as complex as CNS penetration.
这封信件描述了一种新型三环三唑并和咪唑并吡啶内酰胺核心的毒蕈碱乙酰胆碱受体亚型 1（M）正变构调节剂（PAMs）的化学优化，这些化合物不具有 M 激动作用，例如，在高表达重组细胞系中没有 M ago-PAM 活性。虽然所有新的三环同系物都具有优异的大鼠药代动力学（PK）特性（CL < 8 mL/min/kg 和 t > 5 h），但区域异构体三唑并吡啶类似物都没有穿过中枢神经系统（K < 0.05），尽管缺乏氢键供体。然而，去除一个氮原子以提供咪唑并吡啶衍生物被证明保留了优异的大鼠 PK 特性，并提供了高的中枢神经系统穿透性（K > 2），尽管包含了一个碱性氮。此外，24c 在高表达重组细胞系中没有 M 激动作用，并且在体内也没有在小鼠中引起胆碱能发作。有趣的是，所有新的 M PAMs 都具有等效的中枢神经系统 MPO 评分（>4.5），横跨不同的三环杂环核心，这突出了“药物化学家的眼光”和实验数据的价值，例如，不仅仅依赖（或决策偏见）于计算性质等复杂参数的计算，例如中枢神经系统穿透性。
