Department of Medicinal Chemistry, Biocon Bristol Myers Squibb R&D Centre, Biocon Park, Bommasandra Phase IV, Bangalore, PIN 560099, India.
School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Chem Soc Rev. 2024 Feb 19;53(4):2099-2210. doi: 10.1039/d2cs00957a.
The delivery of a drug to a specific organ or tissue at an efficacious concentration is the pharmacokinetic (PK) hallmark of promoting effective pharmacological action at a target site with an acceptable safety profile. Sub-optimal pharmaceutical or ADME profiles of drug candidates, which can often be a function of inherently poor physicochemical properties, pose significant challenges to drug discovery and development teams and may contribute to high compound attrition rates. Medicinal chemists have exploited prodrugs as an informed strategy to productively enhance the profiles of new chemical entities by optimizing the physicochemical, biopharmaceutical, and pharmacokinetic properties as well as selectively delivering a molecule to the site of action as a means of addressing a range of limitations. While discovery scientists have traditionally employed prodrugs to improve solubility and membrane permeability, the growing sophistication of prodrug technologies has enabled a significant expansion of their scope and applications as an empowering tool to mitigate a broad range of drug delivery challenges. Prodrugs have emerged as successful solutions to resolve non-linear exposure, inadequate exposure to support toxicological studies, pH-dependent absorption, high pill burden, formulation challenges, lack of feasibility of developing solid and liquid dosage forms, first-pass metabolism, high dosing frequency translating to reduced patient compliance and poor site-specific drug delivery. During the period 2012-2022, the US Food and Drug Administration (FDA) approved 50 prodrugs, which amounts to 13% of approved small molecule drugs, reflecting both the importance and success of implementing prodrug approaches in the pursuit of developing safe and effective drugs to address unmet medical needs.
将药物递送到特定器官或组织中以达到有效的浓度是促进药物在靶部位发挥有效药理作用并具有可接受安全性的药代动力学（PK）特征。候选药物的药物制剂或 ADME 特征不理想，这通常是由于固有较差的物理化学性质所致，这给药物发现和开发团队带来了重大挑战，并可能导致化合物淘汰率较高。药物化学家已经将前药作为一种明智的策略加以利用，通过优化物理化学、生物制药和药代动力学特性，并选择性地将分子递送到作用部位，从而提高新化学实体的特性，以此来解决一系列限制问题。虽然发现科学家传统上采用前药来提高溶解度和膜通透性，但前药技术的日益成熟使其应用范围和应用领域得到了显著扩大，成为一种有力的工具，可以减轻广泛的药物传递挑战。前药已成为解决非线性暴露、支持毒理学研究的暴露不足、pH 依赖性吸收、高药丸负担、制剂挑战、开发固体制剂和液体制剂缺乏可行性、首过代谢、高给药频率导致患者顺应性降低和药物局部递送不佳等问题的成功解决方案。在 2012 年至 2022 年期间，美国食品和药物管理局（FDA）批准了 50 种前药，占批准的小分子药物的 13%，这反映了在开发安全有效的药物以满足未满足的医疗需求方面实施前药方法的重要性和成功。
