构效关系指导的首创药物托伐普坦

发布时间：2018-02-16 09:48

本文关键词： 构效关系新药创制物化性质技术创造医疗效果智力活动化合物结构体外活性反复验证受体结合 　出处：《药学学报》2017年10期 　论文类型：期刊论文

【摘要】：新药创制是复杂的智力活动,涉及科学研究、技术创造、产品开发和医疗效果等多维科技活动。每个药物都有自身的研发轨迹,而构建化学结构是最重要的环节,因为它涵盖了药效、药代、安全性和生物药剂学等性质。本栏目以药物化学视角,对有代表性的药物的成功构建,加以剖析和解读。在对受体结构缺乏了解、配体为柔性多肽结构的情况下,首创性小分子药物的研发难度在托伐普坦完全体现了。从普筛两万多个化合物获得的苗头化合物,到批准上市的托伐普坦,骨架结构的多次变换,取代基的反复验证,体外活性评价目标的转轨以及体内外活性的协调,乃至药代和物化性质的优化等,托伐普坦的成功可谓历尽艰辛。文中列举的一百多个结构,只是有代表性的化合物,实际状况要复杂得多。常言说新药的创制是在一个混沌空间里的探索过程,本品是一个实例。
[Abstract]:The creation of new drugs is a complex intellectual activity involving multi-dimensional scientific and technological activities such as scientific research, technological creation, product development and medical effects. Each drug has its own research and development track, and the construction of chemical structures is the most important link. Because it covers the properties of pharmacodynamics, pharmacology, safety and biopharmaceutics.This column analyzes and interprets the successful construction of representative drugs from the perspective of pharmacochemistry. When the ligand is a flexible polypeptide structure, the difficulty of developing the first small molecular drug is fully reflected in Tofaptan. From the seedling compounds obtained from more than 20,000 compounds of Pu sieve to the approved Towaputan, Several transformations of skeleton structure, repeated verification of substituents, transition of activity evaluation targets in vitro and coordination of activities in vivo and in vitro, and even optimization of pharmacological and physicochemical properties, etc. Tovaptan's success has been painstaking. The more than 100 structures listed in this paper are just representative compounds, and the actual situation is much more complicated. As the saying goes, the creation of new drugs is a process of exploration in a chaotic space. This article is an example.
【作者单位】：中国医学科学院北京协和医学院药物研究所;
【分类号】：R972

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