新型口服活性NR2B选择性N-甲基-D-天冬氨酸（NMDA）拮抗剂的发现，即具有降低的人醚-去极化激活的钾离子通道（HERG）结合亲和力的吡啶醇衍生物。
Discovery of novel and orally active NR2B-selective N-methyl-D-aspartate (NMDA) antagonists, pyridinol derivatives with reduced HERG binding affinity.
作者信息
Kawai Makoto, Nakamura Hiroshi, Sakurada Isao, Shimokawa Hirohisa, Tanaka Hirotaka, Matsumizu Miyako, Ando Kazuo, Hattori Kazunari, Ohta Atsuko, Nukui Seiji, Omura Atsushi, Kawamura Mitsuhiro
机构信息
Discovery Chemistry, Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan.
出版信息
Bioorg Med Chem Lett. 2007 Oct 15;17(20):5533-6. doi: 10.1016/j.bmcl.2007.08.039. Epub 2007 Aug 22.
Novel NR2B antagonists with an amide tether were found by an approach to avoid pharmacophoric similarity to dofetilide. Structure-activity relationship investigation led to N-[cis-4-hydroxy-4-(5-hydroxypyridin-2-yl)cyclohexyl]-3-henylpropanamide as an orally active NR2B-subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist with very weak HERG (human ether-a-go-go related gene) binding (IC(50)> 30 microM). This compound exhibited potent in vivo anti-allodynic activity in the mouse partial sciatic nerve ligation (PSL) model (minimum effective dose=10 mg/kg, po).
通过一种避免与多非利特产生药效团相似性的方法，发现了具有酰胺连接链的新型NR2B拮抗剂。构效关系研究得出N-[顺式-4-羟基-4-(5-羟基吡啶-2-基)环己基]-3-苯基丙酰胺，它是一种口服活性的NR2B亚型选择性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，对人类ether-a-go-go相关基因（HERG）的结合力非常弱（IC(50)> 30 microM）。该化合物在小鼠坐骨神经部分结扎（PSL）模型中表现出有效的体内抗痛觉过敏活性（最小有效剂量 = 10 mg/kg，口服）。
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