您的位置：首页 > 论文页面
α7-nAChR激动剂的合成及成药性评价
发表时间：2017-09-15 浏览量：1932 下载量：494
| 全部作者： | 谢冰雪，薛雨，马小卓，张亮仁 |
| 作者单位： | 北京大学药学院 |
| 摘 要： | 目的：研究α7-nAChR激动剂的合成路线以及评价N-[(3R)-1-氮杂双环[2.2.2]辛烷-3-基]-5-苯基中氮茚-2-甲酰胺（化合物X1）的毒性和药物代谢动力学。方法：通过Suziki、Baylis-Hillman、热环化反应等方法合成目标化合物X1. 通过急性毒性试验、豚鼠心电影响试验和药物代谢动力学试验评价化合物的成药性。结果：化合物X1的半数致死量（median lethal dose，LD50）大于2 000 mg/kg，阳性对照物EVP-6124的LD50为1 882.7 mg/kg，均属于低毒化合物。豚鼠心电影响结果显示，化合物X1在10，20 mg/kg时，麻醉豚鼠的QT间期及QTc间期均延长超过了10%；而EVP-6124在10 mg/kg时仍未发生显著的QT间期延长。化合物X1吸收、排泄均较慢，生物利用度为53.2%，可到达脑组织并在脑内蓄积。结论：化合物X1毒性小、吸收排泄慢，可能具有潜在的心脏毒性，可作为候选化合物，为临床研究提供重要数据。 |
| 关 键 词： | 药物化学；精神分裂症；成药性评价；α7-nAChR激动剂 |
| Title： | Synthesis of α7-nAChR agonists drugs and druggability evaluation |
| Author： | XIE Bingxue, XUE Yu, MA Xiaozhuo, ZHANG Liangren |
| Organization： | School of Pharmaceutical Sciences, Peking University |
| Abstract： | Objective: To study the synthesis routes of α7-nAChR agonists and evaluate the toxicity and pharmacokinetics of N-[(3R)-1-azabicyalo [2.2.2] octane-3-yl]-5-phenyl-indolizine-2-carboxamide (compound X1). Methods: Compound X1 was synthesized with Suziki, Baylis-Hillman, thermocyclic reaction, et al. Evaluation on druggability mainly included acute toxicity test, guinea-pigs cardio-toxicity test and pharmacokinetic study. Results: Acute toxicity tests showed that median lethal dose (LD50) of compound X1 was more than 2 000 mg/kg, while that of EVP-6124 was 1 882.7 mg/kg, both blonging to low toxicity compounds. Guinea-pigs cardio-toxicity test illuminated that compound X1 appeared cardio-toxicity. When dose of compound X1 was 10, 20 mg/kg , the QT and QTc in anesthetized guinea-pigs were prolonged by more than 10%. While, EVP-6124 with 10 mg/kg still didn’t occur significant prolongation in QT. Absorption and excretion of compound X1 was slow, of which the bioavailability was 53.2%. Compound X1 could pass the blood brain barrier and accumulated in brain tissue. Conclusion: Compound X1 can be a candidate with low acute toxicity and good pharmacokinetic properties. The study provides significant preclinical data for schizophrenia. |
| Key words： | medicinal chemistry; schizophrenia; druggability evaluation; α7-nAChR agonists |
| 发表期数： | 2017年9月第17期 |
| 引用格式： | 谢冰雪，薛雨，马小卓，等. α7-nAChR激动剂的合成及成药性评价[J]. 中国科技论文在线精品论文，2017，10（17）：1956-1965. |
0
评论数 0请您登录
暂无评论
下载全文
多维论文