Discovery of a Pharmacologically Active Antagonist of the Two-Pore-Domain Potassium Channel K2P9.1 (TASK-3)
Discovery of a Pharmacologically Active Antagonist of the Two-Pore-Domain Potassium Channel K2P9.1 (TASK-3)
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DOI：
10.1002/cmdc.201100351
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发表时间：
2012-01-02
期刊：
影响因子：
3.4
通讯作者：
Renger, John J.
中科院分区：
文献类型：
--
作者：
Coburn, Craig A.;Luo, Yunfu;Renger, John J.
twik相关的酸敏感K+ (K2P9.1, TASK-3)离子通道具有通过影响其表达的神经元的静息膜电位来调节神经元通路活性的能力。中枢神经系统（CNS）中这些通道的表达提示了在神经系统疾病中的潜在作用，并且人们相信TASK-3拮抗剂的开发可能导致许多神经系统疾病的治疗性治疗。虽然存在TASK-3通道调节的治疗潜力，但只有少数文献记载的有效和选择性小分子通道阻滞剂的例子。在此，我们描述了基于5,6,7,8-四氢吡啶[4,3-d]嘧啶高通量筛选先导物的一系列新的TASK-3通道拮抗剂的发现和先导物优化工作，从中鉴定了一系列有效的选择性抑制剂。在啮齿动物脑电图遥测模型中，我们对一种化合物的物理特性进行了详细的描述，并通过其调节睡眠结构的能力证明了其药理靶标作用。
TWIK-related acid-sensitive K+ (K2P9.1, TASK-3) ion channels have the capacity to regulate the activity of neuronal pathways by influencing the resting membrane potential of neurons on which they are expressed. The central nervous system (CNS) expression of these channels suggests potential roles in neurologic disorders, and it is believed that the development of TASK-3 antagonists could lead to the therapeutic treatment of a number of neurological conditions. While a therapeutic potential for TASK-3 channel modulation exists, there are only a few documented examples of potent and selective small-molecule channel blockers. Herein, we describe the discovery and lead optimization efforts for a novel series of TASK-3 channel antagonists based on a 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine high-throughput screening lead from which a subseries of potent and selective inhibitors were identified. One compound was profiled in detail with respect to its physical properties and demonstrated pharmacological target engagement as indicated by its ability to modulate sleep architecture in rodent electroencephalogram (EEG) telemetry models.