先导化合物结构优化策略(二)——结构修饰降低潜在毒性

Lead compound optimization strategy (2)——structure optimization strategy for reducing toxicity risks in drug design

摘要: 药物特质性毒性反应能够引发严重的药物毒副作用甚至危及患者生命。含有警惕结构的药物在体内能够产生活性代谢物，这是药物发生特质性毒性反应的一个重要原因。优化药物分子中的警惕结构以及通过结构改造避免警惕结构产生活性代谢物，是药物早期研发中降低药物毒性风险的重要手段。本文通过比对上市与撤市药物，运用实例阐述降低药物毒性风险的结构改造策略，包括封闭代谢位点、改变代谢途径、降低警惕结构反应性、生物电子等排以及前药等。

Abstract: Idiosyncratic adverse drug reactions (IDR) induce severe medical complications or even death in patients. Alert structure in drugs can be metabolized as reactive metabolite (RM) in the bodies, which is one of the major factors to induce IDR. Structure modification and avoidance of alert structure in the drug candidates is an efficient method for reducing toxicity risks in drug design. This review briefly summarized the recent development of the methodologies for structure optimization strategy to reduce the toxicity risks of drug candidates. These methods include blocking metabolic site, altering metabolic pathway, reducing activity, bioisosterism, and prodrug.