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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。
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 development trajectory, and the construction of the chemical structure is the most important part, because it covers the properties such as efficacy, drug substitution, safety and biopharmaceutical. This column from the perspective of medicinal chemistry, representative of the successful construction of drugs, to be analyzed and interpreted. In the lack of understanding of the receptor structure, the ligand for the flexible polypeptide structure, the development of innovative small molecule drugs in the difficulty of fully demonstrated in tolbutamide. From the screening of more than 20,000 compounds obtained from the signs of the compound to the approved listing of tolvaptan, multiple changes in the framework of the structure, repeated verification of substituents, in vitro activity evaluation of the goal of the transition and coordination of in vitro and in vivo activity, and even medicine The optimization of physico-chemical properties and so on, the success of tolvaptan can be described as experiencing hardships. The more than 100 structures enumerated in this paper represent only representative compounds, and the actual situation is much more complex. Often said that the creation of new drugs in a chaotic space exploration process, this product is an example.