Li Ziying, Xiao Xinyi, Xue Yulin, Zhou Huiling, Huang Chaonan, Zhu Mo, Zhuang Tao, Chen Yin, Huang Ling
Jiangsu Institute of Marine Resources Development, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Ocean University, Lianyungang 222005, China.
Grand Life Sciences (Wuhan) Co., Ltd., Wuhan 430040, China.
Bioorg Chem. 2022 Oct;127:106039. doi: 10.1016/j.bioorg.2022.106039. Epub 2022 Jul 19.
To discover effective analgesics, we summarize the synthesis, optimization, and pharmacological anti-nociceptive effects of a novel series of benzoxazole derivatives targeting H receptor (HR). The new benzoxazoles were assayed in vitro for histamine HR and HR binding affinity. The best compound 8d (2-methyl-6-(3-(4-methylpiperazin-1-yl)propoxy)benzo[d]oxazole) exhibited high affinity for HR (K = 19.7 nM), high selectivity for ten other off-target receptors, and negligible effects on human ether-a-go-go-related gene (hERG, cardiac ion channel). In rodent animals, compound 8d dose-dependently reversed formalin-evoked pain (Phase I, ED = 6.0 mg/kg; Phase II, ED = 7.8 mg/kg) and CCI-induced neuropathic pain (chronic constriction injury, ED = 15.6 mg/kg). Furthermore, compound 8d showed an excellent safety profile in acute toxicity test (LD > 2000 mg/kg) with a therapeutic index (TI = LD/ED) > 250 and showed a desirable drug-like pharmacokinetic profile. Above characteristics indicate that compound 8d represents a promising candidate analgesic for the treatment of neuropathic pain.
为了发现有效的镇痛药，我们总结了一系列靶向H受体（HR）的新型苯并恶唑衍生物的合成、优化及其药理学抗伤害感受作用。对新的苯并恶唑进行了组胺HR和HR结合亲和力的体外测定。最佳化合物8d（2-甲基-6-(3-(4-甲基哌嗪-1-基)丙氧基)苯并[d]恶唑）对HR表现出高亲和力（K = 19.7 nM），对其他十种脱靶受体具有高选择性，并且对人醚-去极化相关基因（hERG，心脏离子通道）的影响可忽略不计。在啮齿动物中，化合物8d剂量依赖性地逆转福尔马林诱发的疼痛（第一阶段，ED = 6.0 mg/kg；第二阶段，ED = 7.8 mg/kg）和CCI诱导的神经性疼痛（慢性压迫损伤，ED = 15.6 mg/kg）。此外，化合物8d在急性毒性试验中显示出优异的安全性（LD > 2000 mg/kg），治疗指数（TI = LD/ED）> 250，并且显示出理想的类药物药代动力学特征。上述特征表明化合物8d是治疗神经性疼痛的有前景的候选镇痛药。
