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α7-nAChR激动剂的合成及成药性评价

发表时间:2017-09-15  浏览量:915  下载量:122
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.
 
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