Discovery of a Selective Allosteric M1 Receptor Modulator with Suitable Development Properties Based on a Quinolizidinone Carboxylic Acid Scaffold
Discovery of a Selective Allosteric M1 Receptor Modulator with Suitable Development Properties Based on a Quinolizidinone Carboxylic Acid Scaffold
复制标题
DOI：
10.1021/jm200400m
复制
发表时间：
2011-07-14
影响因子：
7.3
通讯作者：
Rays, William J.
中科院分区：
文献类型：
--
作者：
Kuduk, Scott D.;Chang, Ronald K.;Rays, William J.
改善阿尔茨海默病 (AD) 认知能力下降的一种方法是通过激活 M-1 毒蕈碱受体来恢复基底前脑胆碱能系统的神经元信号传导。许多非选择性 M-1 毒蕈碱激动剂先前已显示出对 AD 患者认知行为的积极作用，但由于胆碱能不良事件被认为是由 M-2 至 M-5 亚型激活介导的，因此效果有限。赋予 M-1 选择性的一种策略是鉴定正变构调节剂，该调节剂将靶向 M-1 受体上的变构位点，而不是高度保守的正构乙酰胆碱结合位点。我之前已将喹啉羧酸鉴定为高度选择性的 M-1 正变构调节剂，具有良好的药代动力学和体内特性。本文描述了新型喹嗪酮羧酸支架与 4-氰基哌啶的优化，这是增强活性方面的关键发现。特别是，调节剂 4i 提供高血浆游离分数，增强中枢神经系统 (CNS) 暴露，在啮齿动物体内认知模型中有效，并提供适合进一步临床前评估的良好理化性质。
One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M-1 muscarinic receptor. A number of nonselective M-1 muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M-2 to M-5 subtypes. One strategy to confer selectivity for M-1 is the identification of positive allosteric modulators, which would target an allosteric site on the M-1 receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have I been previously identified as highly selective M-1 positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.