Department of Medicinal Chemistry, Merck Research Laboratories, Boston, MA, USA.
Bioorg Med Chem Lett. 2010 Aug 1;20(15):4704-8. doi: 10.1016/j.bmcl.2010.04.016. Epub 2010 Apr 13.
A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.
报告了一种新型的神经肽 S 受体（NPSR）强效拮抗剂结构类别。高通量筛选鉴定出一种 NPSR 的三环咪唑拮抗剂，对该结构进行药物化学优化以提高对受体的效力以及中枢神经系统穿透性。本文详细介绍了导致鉴定出拮抗剂 15 和 NPSR-PI1 的合成和药物化学研究，它们在体内表现出强效的体外 NPSR 拮抗作用和中枢暴露。
