Weiss Dahlia R, Baylon Javier L, Evans Ethan D, Paiva Anthony, Everlof Gerry, Cutrone Jingfang, Broccatelli Fabio
Bristol-Myers Squibb Company, Redwood City, California 94063, United States.
Bristol-Myers Squibb Company, San Diego, California 92121, United States.
ACS Med Chem Lett. 2024 Mar 19;15(4):457-462. doi: 10.1021/acsmedchemlett.3c00542. eCollection 2024 Apr 11.
The optimization of passive permeability is a key objective for orally available small molecule drug candidates. For drugs targeting the central nervous system (CNS), minimizing P-gp-mediated efflux is an additional important target for optimization. The physicochemical properties most strongly associated with high passive permeability and lower P-gp efflux are size, polarity, and lipophilicity. In this study, a new metric called the Balanced Permeability Index (BPI) was developed that combines these three properties. The BPI was found to be more effective than any single property in classifying molecules based on their permeability and efflux across a diverse range of chemicals and assays. BPI is easy to understand, allowing researchers to make decisions about which properties to prioritize during the drug development process.
被动渗透性的优化是口服小分子候选药物的一个关键目标。对于靶向中枢神经系统（CNS）的药物，将P-糖蛋白介导的外排降至最低是优化的另一个重要目标。与高被动渗透性和较低P-糖蛋白外排最密切相关的物理化学性质是大小、极性和亲脂性。在本研究中，开发了一种名为平衡渗透指数（BPI）的新指标，它综合了这三种性质。结果发现，在根据各种化学物质和试验的渗透性和外排对分子进行分类方面，BPI比任何单一性质都更有效。BPI易于理解，使研究人员能够在药物开发过程中决定优先考虑哪些性质。
