Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, United States.
J Med Chem. 2011 Jul 14;54(13):4773-80. doi: 10.1021/jm200400m. Epub 2011 Jun 17.
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 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.
一种改善阿尔茨海默病（AD）认知能力下降的方法是通过激活 M1 毒蕈碱受体来恢复基底前脑胆碱能系统的神经元信号。先前有许多非选择性 M1 毒蕈碱激动剂显示出对 AD 患者认知行为的积极影响，但由于认为是通过激活 M2 到 M5 亚型介导的胆碱能不良反应而受到限制。赋予 M1 选择性的一种策略是鉴定正变构调节剂，其将针对 M1 受体的变构位点而不是高度保守的同型乙酰胆碱结合位点。先前已经鉴定出喹啉羧酸作为高度选择性的 M1 正变构调节剂，具有良好的药代动力学和体内特性。本文描述了一种新型喹唑啉酮羧酸支架的优化，其中 4-氰基哌啶是提高活性的关键发现。特别是调节剂 4i 具有较高的血浆游离分数、增强的中枢神经系统（CNS）暴露，在啮齿动物认知体内模型中有效，并具有良好的适合进一步临床前评估的理化性质。
