盐酸他克林前体药物的研究盐酸他克林前体药物的研究

目的制备盐酸他克林(THA)的酰化前体药物以提高其透过血脑屏障(BBB)的能力。方法THA和酸酐反应制得N-酰化-THA系列前体药物;考察了前体药物在不同介质中的降解情况,并以N-单丁酰-他克林(BTHA)为模型药物,考察其在小鼠体内的分布和降解情况。结果合成的化合物经¹HNMR,MS和IR鉴定为目标化合物。前体药物在不同介质中均较稳定。与原药相比,前药的脂水分布系数增大。BTHA主要分布于脑、血浆和肝脏中(最高浓度分别为17.572 5,13.140 0和22.827 9 mg·L^-1),在肺和心中的分布浓度很低(最高浓度分别为4.947 5和4.492 5 mg·L^-1)。BTHA在脑内的降解速率较慢,给药12 h后仍有较高浓度(2.415 9 mg·L^-1)。结论N-羧酰-THA系列前体药物提高了THA透过BBB的能力,有望成为脑内定向给药的有效途径。

Synthesis of prodrugs of tacrine hydrochloride and evaluation of the stability and biodistribution in mice

AIM: To synthesize acylated prodrug of tacrine hydrochloride (THA) to improve the infiltration ability across the blood brain barrier (BBB). METHODS: A series of prodrugs were prepared by acylation of the 7-amino group of THA. The degradation of prodrugs was investigated under different conditions. Biodistribution studies of N-butyramide-THA (BTHA) in mice were carried out to evaluate the function of brain targeting. RESULTS: The structures of prodrugs were confirmed by IR, 1HNMR and MS. All prodrugs were stable in different medium. Octanol-water partition coefficients indicated increased lipophlicity for various prodrugs compared to the THA. In vivo distribution studies showed that BTHA was mainly distributed in brain, blood and liver (the maximum concentrations were 17.5725, 13.1400 and 22.8279 mg.L-1, respectively), while the THA concentration were very low in lung and heart (the maximum concentrations were 4.9475 and 4.4925 mg.L-1, respectively). The BTHA concentration (2.4159 mg.L-1) was relatively high even 12 h after administration, showing that BTHA degraded more slowly in brain than in other tissues. CONCLUSION: The infiltration ability of THA across BBB was increased in the form of N-acylate-THA prodrug, indicating that this kind of prodrug is a promising brain-targeting delivery system.