Developing orally bioavailable drugs demands an understanding of absorption in early drug development. Traditional methods and physicochemical properties optimize absorption for rule of five (Ro5) compounds; beyond rule of five (bRo5) drugs necessitate advanced tools like the experimental measure of exposed polarity (EPSA) and the AbbVie multiparametric score (AB-MPS). Analyzing AB-MPS and EPSA against ∼1000 compounds with human absorption data and ∼10,000 AbbVie tool compounds (∼1000 proteolysis targeting chimeras or PROTACs, ∼7000 Ro5s, and ∼2000 bRo5s) revealed new patterns of physicochemical trends. We introduced a high-throughput “polarity reduction” descriptor: ETR, the EPSA-to-topological polar surface area (TPSA) ratio, highlights unique bRo5 and PROTAC subsets for specialized drug design strategies for effective absorption. Our methods and guidelines refine drug design by providing innovative in vitro approaches, enhancing physicochemical property optimization, and enabling accurate predictions of intestinal absorption in the complex bRo5 domain.

中文翻译：

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现代药物发现中超越五法则和 PROTAC：极性降低剂、变色性和不断变化的物理化学景观

开发口服生物可利用的药物需要了解早期药物开发的吸收。传统方法和理化性质优化了五元规则 (Ro5) 化合物的吸收；超越五规则 (bRo5) 药物需要先进的工具，例如暴露极性实验测量 (EPSA) 和艾伯维多参数评分 (AB-MPS)。针对约 1000 种具有人体吸收数据的化合物和约 10,000 种艾伯维工具化合物（约 1000 种针对嵌合体或 PROTAC 的蛋白水解、约 7000 个 Ro5 和约 2000 个 bRo5）分析 AB-MPS 和 EPSA，揭示了理化趋势的新模式。我们引入了高通量“极性降低”描述符：ETR，即 EPSA 与拓扑极性表面积 (TPSA) 之比，突出了独特的 bRo5 和 PROTAC 子集，用于专门的药物设计策略，以实现有效吸收。我们的方法和指南通过提供创新的体外方法、增强理化性质优化以及准确预测复杂 bRo5 结构域的肠道吸收来完善药物设计。