Kawai Makoto, Nakamura Hiroshi, Sakurada Isao, Shimokawa Hirohisa, Tanaka Hirotaka, Matsumizu Miyako, Ando Kazuo, Hattori Kazunari, Ohta Atsuko, Nukui Seiji, Omura Atsushi, Kawamura Mitsuhiro
Discovery Chemistry, Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan.
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）。
