Department of Pharmaceutical Chemistry, Faculty of Pharmacy & Biotechnology, German University in Cairo - GUC, Egypt.
J Pharm Biomed Anal. 2011 Nov 1;56(3):569-76. doi: 10.1016/j.jpba.2011.06.023. Epub 2011 Jul 1.
Baclofen exhibits insufficient CNS-availability when dosed systemically. Hence, prodrug candidates (methyl, ethyl, 1-propyl, 2-propyl and butyl 4-(tert-butoxycarbonyl amino)-3-(4-chlorophenyl) butanoate) were synthesized aiming at CNS-levels appropriate for the treatment of spastic disorders. The characterization of some biopharmaceutically highly relevant physicochemical properties (LogP and aqueous solubility) and the evaluation of biophase levels represent one important component of the project. The overall research aim was to generate an HPLC optimized method using DryLab, a simulation software for the optimization of a RP-HPLC method, which was optimized using a simulation software (DryLab), for the simultaneous determination of baclofen and ten synthesized prodrug candidates. The chromatographic resolution predicted and obtained via the simulation is Rs >1.5 for all baclofen derivatives, as well as, with parent baclofen. The method was used to assay the prodrugs and determine their purities, solubility and lipophilicity parameters. The designed analytical method also permits the tracking of the new prodrug candidates' hydrolysis in vitro and in vivo. The determined physicochemical properties indicate for some of the compounds that they might be suitable for CNS-targeting which was exemplified by the detection of significant baclofen levels in rat brain tissues following an i.p. dose of ethyl carbamate (vs. ethyl ester, for which only traces of baclofen were detected).
巴氯芬经全身给药时中枢神经系统（CNS）的利用率不足。因此，我们合成了前药候选物（甲酯、乙酯、1-丙酯、2-丙酯和丁酯 4-（叔丁氧羰基氨基）-3-（4-氯苯基）丁酸酯），旨在达到治疗痉挛障碍的合适的CNS 水平。一些具有重要生物药剂学性质（LogP 和水溶解度）的特征描述和生物相水平的评估是该项目的一个重要组成部分。总的研究目的是生成一种使用 DryLab 优化的 HPLC 方法，这是一种用于优化反相高效液相色谱法（RP-HPLC）的模拟软件，我们使用该模拟软件优化了一种同时测定巴氯芬和十种合成前药候选物的方法。通过模拟预测和获得的色谱分辨率对于所有巴氯芬衍生物以及母体巴氯芬均为 Rs >1.5。该方法用于测定前药的纯度、溶解度和脂溶性参数。所设计的分析方法还允许追踪新前药候选物在体外和体内的水解情况。所确定的物理化学性质表明，一些化合物可能适合 CNS 靶向，这可以通过检测到腹腔内给予氨基甲酸乙酯（与乙酯相比，仅检测到痕量的巴氯芬）后大鼠脑组织中的巴氯芬水平得到证明。
