二氢吡啶类钙拮抗剂结构与药物动力学的定量关系分析

Study on quantitative structures- pharmacokinetic relationship of dipyridines calcium ion antagonists

目的 :研究二氢吡啶类钙拮抗剂的化学结构与药物动力学的关系 ,为新药设计中早期筛选提供理论方法。方法 :采用InsightⅡ软件的分子力学和分子动力学程序首先将钙拮抗剂的结构式转化为三维结构 ,并进行能量优化 ,使得结构趋于合理。Hy perChem软件计算优化好的结构的理化性质参数(LogP ,SurfaceArea ,Volume ,HydrationEnergy ,Refrac tivity ,Polarizability)。对钙拮抗剂药物的理化参数与其药物动力学参数之间关系进行统计分析研究。结果 :钙拮抗剂的疏水性常数 (LogP)值与血管外给药后的达峰时间 (Tmax)存在二次方程关系 ,二者的相关性达到 0 .9以上。结论 :二氢吡啶类钙拮抗剂药物的疏水性常数 (LogP)值与给药后的达峰时间 (Tmax)存在的关系对该类药物的进一步结构改造 ,设计新药具有重要的指导意义。

AIM: To study on the quantitative structures- pharmacokinetic relationship of dipyridines calcium ion antagonists to provide the theoretic method to screen new drugs in early period. METHODS: The structures of calcium ion antagonists were conversed from two to three dimensional structure by Insight Ⅱ Program. The conversed structures were optimized to the minimum energy by the steepest descent and conjugate gradient methods. The physico-chemical parameters of the optimized structures, including Log P, surface area, volume, hydration energy, refractivity and polarizability, were calculated by HyperChem Program. The interrelation between structures and pharmacokinetic parameters for calcium ionantagonists was analyzed. RESULTS: There was a good correlation between the hydrophobicity constants (Log P) and the reached peak time (T max) after extravenous administration of the calcium ion antagonists to the subjects. The correlation coefficient was over 0.9. CONCLUSION: The correlation between the chemical structure and its pharmacokinetic parameters can provide instructions to new drug design for calcium ion antagonists.