Judge Susan I V, Smith Paul J
University of Maryland School of Medicine, MS Center of Excellence-East, VA Maryland Health Care System, Department of Neurology, BRB 12-040, 655 West Baltimore Street, Baltimore, MD 21201, USA.
Expert Opin Ther Pat. 2009 Apr;19(4):433-60. doi: 10.1517/13543770902765151.
Mechanisms of neuroprotection encompass energy deficits in brain arising from insufficient oxygen and glucose levels following respiratory failure; ischemia or stroke, which produce metabolic stresses that lead to unconsciousness and seizures; and the effects of general anesthetics. Foremost among those K(+) channels viewed as important for neuroprotection are ATP-sensitive (K(ATP)) channels, which belong to the family of inwardly rectifying K(+) channels (K(ir)) and contain a sulfonylurea subunit (SUR1 or SUR2) combined with either K(ir)6.1 (KCNJ8) or K(ir)6.2 (KCNJ11) channel pore-forming alpha-subunits, and various members of the tandem two-pore or background (K(2P)) K(+) channel family, including K(2P)1.1 (KCNK1 or TWIK1), K(2P)2.1 (KCNK2 or TREK/TREK1), K(2P)3.1 (KCNK3 or TASK), K(2P)4.1 (KCNK4 or TRAAK), and K(2P)10.1 (KCNK10 or TREK2).
This review covers patents and patent applications related to inventions of therapeutics, compound screening methods and diagnostics, including K(ATP) channel openers and blockers, as well as K(ATP) and K(2P) nucleic/amino acid sequences and proteins, vectors, transformed cells and transgenic animals. Although the focus of this patent review is on brain and neuroprotection, patents covering inventions of K(ATP) channel openers for cardioprotection, diabetes mellitus and obesity, where relevant, are addressed.
RESULTS/CONCLUSIONS: Overall, an important emerging therapeutic mechanism underlying neuroprotection is activation/opening of K(ATP) and K(2P) channels. To this end substantial progress has been made in identifying and patenting agents that target K(ATP) channels. However, current K(2P) channels patents encompass compound screening and diagnostics methodologies, reflecting an earlier 'discovery' stage (target identification/validation) than K(ATP) in the drug development pipeline; this reveals a wide-open field for the discovery and development of K(2P)-targeting compounds.
神经保护机制包括呼吸衰竭后因氧气和葡萄糖水平不足而导致的脑部能量缺乏；缺血或中风，其产生导致昏迷和癫痫发作的代谢应激；以及全身麻醉剂的作用。在那些被认为对神经保护很重要的钾通道中，最重要的是ATP敏感性（KATP）通道，它属于内向整流钾通道（Kir）家族，包含一个磺酰脲亚基（SUR1或SUR2）与Kir6.1（KCNJ8）或Kir6.2（KCNJ11）通道孔形成α亚基结合，以及串联双孔或背景（K2P）钾通道家族的各种成员，包括K2P1.1（KCNK1或TWIK1）、K2P2.1（KCNK2或TREK/TREK1）、K2P3.1（KCNK3或TASK）、K2P4.1（KCNK4或TRAAK）和K2P10.1（KCNK10或TREK2）。
本综述涵盖与治疗学、化合物筛选方法和诊断学发明相关的专利和专利申请，包括KATP通道开放剂和阻滞剂，以及KATP和K2P核酸/氨基酸序列和蛋白质、载体、转化细胞和转基因动物。尽管本专利综述的重点是脑和神经保护，但在相关情况下，也涉及涵盖用于心脏保护、糖尿病和肥胖症的KATP通道开放剂发明的专利。
结果/结论：总体而言，神经保护潜在的一种重要新兴治疗机制是KATP和K2P通道的激活/开放。为此，在识别靶向KATP通道的药物并为其申请专利方面已取得了重大进展。然而，目前关于K2P通道的专利涵盖化合物筛选和诊断方法，这反映出在药物开发流程中，K2P通道处于比KATP通道更早的“发现”阶段（靶点识别/验证）；这表明发现和开发靶向K2P的化合物存在广阔空间。
