Liguzinediol缬氨酸酯前药的设计、合成及成药性评价
Design， Synthesis and Druggability Evaluation of Liguzinediol Valine Ester Prodrug as Promissing Inotropic Agent
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摘要: 目的 设计、合成liguzinediol缬氨酸酯前药，结合化学稳定性、理化性质、体外生物转化和体内药代动力学研究，为进一步liguzinediol氨基酸酯类前药研究奠定基础。方法 以liguzinediol和N-叔丁氧羰基(Boc)-L-缬氨酸为原料，经4-二甲氨基吡啶（DMAP）催化、N，N'-二环己基碳二亚胺（DCC）缩合成酯，15% TFA脱Boc保护得liguzinediol缬氨酸酯前药，目标化合物结构经LC-HRMS、1H-NMR和13C-NMR确证。采用高效液相色谱法（HPLC）测定目标化合物的化学稳定性、溶解度、容量因子和脂水分配系数，以及体外80%人体血浆中酯酶水解的释放特性和体内药代动力学研究。结果 Liguzinediol缬氨酸酯前药保留了原药的溶解度特性，体外80%人体血浆酶解liguzinediol释放速率良好，体内作用时间明显延长；但脂溶性相对较差。结论 Liguzinediol缬氨酸酯前药具有一定的成药性，且明显延长了原药 liguzinediol的体内作用时间，为进一步liguzinediol氨基酸酯前药研究提供了思路。Abstract: OBJECTIVE One liguzinediol valine ester prodrug was synthesized and evaluated for the physicochemical properties and bioconversion， which laid the foundation for further study of liguzinediol amino acid ester prodrugs. METHODS Liguzinediol valine ester prodrug was prepared by a two-step reaction of condensation and deprotection from liguzinediol， and its structure was verified by LC-HRMS， 1H-NMR and 13C-NMR. The chemical stability， capacity factor， solubility， lipophilicity， metabolic stability in human plasma and pharmacokinetics study in vivo of valine ester prodrug were tested by HPLC. RESULTS Liguzinediol valine ester prodrug retained great solubility and showed good bioconversion in human plasma. The half-time of liguzinediol was extended obviously. However， the lipophilicity was relatively poor. CONCLUSION Liguzinediol valine ester prodrug was provided with the feature to form the drug， and obvious extended the half-time of liguzinediol. Meanwhile， it indicated that prodrug strategy was feasible， which provided the way of experiment for liguzinediol prodrug research.
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