School of Pharmacy, Jinzhou Medical University, Jinzhou, Liaoning, 121001, China.
State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100050, China.
Sci Rep. 2019 Feb 19;9(1):2247. doi: 10.1038/s41598-019-38911-1.
The neuroprotective agent 3-hydroxymorphinan (3-HM) is a well-documented and highly safe therapeutic intervention for the inflammatory-related effects of Parkinson's disease (PD). However, the bioavailability of 3-HM is very low due to the rapid first-pass metabolism of the phenolic moiety. In the present study, we sought to improve the metabolic stability and overall pharmacokinetic profile of 3-HM. Based on an iterative design process that a suitably arranged heterocycle with an NH group would serve as the metabolically stable isostere of the phenolic group, we designed and synthesized two analogues of 3-HM. Benzimidazolone compound 8 (imidazolone-morphinan) was comparable in activity to 3-HM against lipopolysaccharide (LPS)-induced inflammatory responses in microglial BV2 cells and in vivo animal experiments (MPTP-induced PD mouse model). Moreover, the in vitro study showed that imidazolone-morphinan was non-toxic to microglia, indicating its high safety. Considering the favourable and unique preclinical profiles, compound 8 was nominated as a candidate for further clinical development.
神经保护剂 3-羟吗啡烷（3-HM）是一种经过充分证实且高度安全的治疗帕金森病（PD）炎症相关影响的治疗方法。然而，由于酚部分的快速首过代谢，3-HM 的生物利用度非常低。在本研究中，我们试图提高 3-HM 的代谢稳定性和整体药代动力学特征。基于这样一个迭代设计过程：一个适当排列的带有 NH 基团的杂环将作为酚基团的代谢稳定等排物，我们设计并合成了 3-HM 的两个类似物。苯并咪唑酮化合物 8（咪唑酮吗啡烷）在体外实验（脂多糖（LPS）诱导的小胶质细胞 BV2 细胞炎症反应和体内动物实验（MPTP 诱导的 PD 小鼠模型）中与 3-HM 相比具有相当的活性。此外，体外研究表明，咪唑酮吗啡烷对小胶质细胞无毒，表明其安全性高。考虑到有利和独特的临床前特征，化合物 8 被选为进一步临床开发的候选药物。
