Pollastri Michael P
Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA.
Curr Protoc Pharmacol. 2010 Jun;Chapter 9:Unit 9.12. doi: 10.1002/0471141755.ph0912s49.
In the mid- to late 1990 s, because of the drug discovery paradigm shift from phenotypic screens to combinatorial chemistry and high-throughput screening, the physicochemical properties of exploratory drug molecules displayed a dramatic shift toward higher molecular weight and lipophilicity. In response, Lipinski and coworkers reported an analysis of compounds that successfully navigated Phase I and entered into Phase II clinical studies, and correlated the computed physicochemical properties of these molecules to their aqueous solubility, permeability, and oral bioavailability. In doing so, the authors created the "Rule of Five," a mnemonic tool for medicinal chemists to use to quickly assess compounds during the drug discovery and optimization process with respect to the compounds' likelihood to display good solubility and permeability profiles. This overview outlines the basis for the Rule of Five, the ways in which it has been applied, and its impact on drug discovery and development.
在20世纪90年代中后期，由于药物发现模式从表型筛选转向组合化学和高通量筛选，探索性药物分子的物理化学性质呈现出向更高分子量和亲脂性的显著转变。作为回应，利平斯基及其同事报告了对成功通过一期试验并进入二期临床研究的化合物的分析，并将这些分子的计算物理化学性质与其水溶性、渗透性和口服生物利用度相关联。通过这样做，作者创建了“五规则”，这是一种助记工具，供药物化学家在药物发现和优化过程中用于快速评估化合物显示良好溶解度和渗透性特征的可能性。本综述概述了五规则的基础、其应用方式及其对药物发现和开发的影响。
