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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。雷特格韦是针对治疗艾滋病的整合酶抑制剂,为首创性药物。由普筛得到的二酮酸苗头化合物引申出干预催化中心的二价镁离子的螯合机制。将苗头物中的螯合基团,移植到类药的骨架上,再作适当的结构修饰,完成了苗头向先导物的过渡(hit-to-lead)。后继的优化是在多维度空间中进行的,包括增强抑制整合酶活性,提高选择性,促进过膜性,改善物化性质,降低脱靶作用(off-targeting)和血浆蛋白结合等。在由活性化合物向成药的转化中,数个里程碑式的化合物既可视做伴随研发的候选物(back-up candidate),也为本品的成功提供了可贵的借鉴。
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. Levogavir is an integrase inhibitor for the treatment of AIDS and is the first of its kind. The diketo acid triterpene compounds obtained from Sift showed a mechanism of chelation that interferes with the divalent magnesium ion of the catalytic center. The chelating groups in the shoots are transplanted into the skeleton of the drug-like body, and the appropriate structural modification is performed to complete the hit-to-lead transition. Subsequent optimization is performed in a multidimensional space, including enhanced integrase inhibition, increased selectivity, membrane permeability, improved physicochemical properties, reduced off-targeting and plasma protein binding. In the conversion from active compounds to drugs, several landmark compounds are not only regarded as back-up candidates, but also valuable references for the success of this product.