AQW051, a novel, potent and selective α7 nicotinic ACh receptor partial agonist: pharmacological characterization and phase I evaluation
AQW051, a novel, potent and selective α7 nicotinic ACh receptor partial agonist: pharmacological characterization and phase I evaluation
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DOI：
10.1111/bph.13001
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发表时间：
2015-03-01
影响因子：
7.3
通讯作者：
Lopez Lopez, Cristina
中科院分区：
文献类型：
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作者：
Feuerbach, Dominik;Pezous, Nicole;Lopez Lopez, Cristina
背景与目的激活7烟碱乙酰胆碱受体（nACh受体）被认为是治疗神经系统疾病相关认知障碍的一个有吸引力的靶点。在这里，我们描述了新的7-nACh受体激动剂AQW051作为一个有希望的候选药物用于这种适应症。实验方法：在体外对haqw051进行功能表征，并在啮齿动物行为模型中评估其认知效果。在180名健康受试者的三个I期安慰剂对照研究中评估了药代动力学和耐受性。关键结果在体外，AQW051与7-nACh受体高亲和力结合，在重组表达人7-nACh受体的细胞中刺激钙内流。在体内，AQW051表现出良好的口服生物利用度和快速渗透到啮齿动物大脑的能力。大剂量给药AQW051促进了小鼠的物体识别和社会识别测试以及老年大鼠的水迷宫模型的学习/记忆表现。临床上，AQW051在健康的年轻人和老年人中耐受性良好，不良事件（AE）与安慰剂相当。在单次口服剂量高达200mg和多次每日剂量高达75mg的情况下，未报告严重不良事件，所有不良事件均为轻度或中度严重。每天口服一次AQW051导致持续暴露，并在1周内达到与稳态相比2 - 3倍的积累。结论和意义这些数据支持AQW051作为认知增强剂的进一步开发，例如作为阿尔茨海默病或精神分裂症的治疗药物。
Background and PurposeActivation of the 7 nicotinic ACh receptor (nACh receptor) is considered an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel 7-nACh receptor agonist AQW051 as a promising drug candidate for this indication.Experimental ApproachAQW051 was functionally characterized in vitro and cognitive effects evaluated in rodent behavioural models. Pharmacokinetics and tolerability were evaluated in three phase I placebo-controlled studies in 180 healthy subjects.Key ResultsIn vitro, AQW051 bound with high affinity to 7-nACh receptors and stimulated calcium influx in cells recombinantly expressing the human 7-nACh receptor. In vivo, AQW051 demonstrated good oral bioavailability and rapid penetration into the rodent brain. AQW051 administered over a broad dose range facilitated learning/memory performance in the object recognition and social recognition test in mice and the water maze model in aged rats. Clinically, AQW051 was well tolerated in healthy young and elderly subjects, with an adverse event (AE) profile comparable with placebo. No serious AEs were reported and all AEs were either mild or moderate in severity at single oral doses up to 200mg and multiple daily doses up to 75mg. Once-daily oral administration of AQW051 resulted in continuous exposure and a two- to threefold accumulation compared with steady state was achieved by 1 week.Conclusions and ImplicationsThese data support further development of AQW051 as a cognitive-enhancing agent, as a therapeutic, for example, in Alzheimer's disease or schizophrenia.