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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2013年FDA批准阿格列汀上市之前,已有4个作用于DPP-4的口服治疗2型糖尿病药物。武田药厂研制本品的轨迹表明,并非模拟性药物,而是以结构生物学指引的设计合成的新结构类型,由发现苗头化合物到演化成先导物,由优化到确定候选药物,运用复合物的晶体结构于全过程;在药物化学的骨架迁越、取代基变换以优化选择性和成药性过程中,保持了口服吸收所需的分子尺寸,分子量不仅没有增加,还有所降低,因而阿格列汀有较高的配体效率。本品的结构类型不同于已有的DPP-4抑制剂,因而在结构的层面上具有首创意义。
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. Prior to the FDA’s approval of the listing of alogliptin in 2013, four oral agents for type 2 diabetes have been administered to DPP-4. Takeda Pharmaceutical Factory trajectory of development of this product shows that rather than analog drugs, but based on structural biology guidelines designed and synthesized a new type of structure, from the discovery of the spike compound to evolve into a leader, from optimization to determine the candidate drugs, the use of complexes Crystal structure in the whole process; in the migration of the skeleton of the drug chemistry, the substitution of substituents to optimize the selectivity and drug-induced process, to maintain the molecular size required for oral absorption, the molecular weight not only did not increase, but also decreased, and therefore Mitalin has higher ligand efficiency. The structure of this product is different from the existing DPP-4 inhibitors, and therefore has a first-class meaning at the level of the structure.