Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065, United States.
Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
J Med Chem. 2020 Nov 12;63(21):12156-12170. doi: 10.1021/acs.jmedchem.9b01813. Epub 2020 Jul 7.
Lipophilicity has a dominant effect on many parameters that determine unbound drug exposure as well as drug potency. Despite this, analysis of a large body of drug data indicates lipophilicity has no consistent directional impact on dose. This can be rationalized based on the interplay of the effects of lipophilicity on individual parameter values in pharmacokinetic equations. We believe this undermines the effectiveness of strategies that target specific ranges for drug parameters for which lipophilicity plays such a dominant role. As a result, our research organization no longer leverages the common approach of screening for low intrinsic clearance to target high unbound exposure . Instead, we advocate for approaches less biased to lipophilicity through optimization of key parameter ratios controlling dose. We believe this improves efficiency in drug discovery by enabling exploration of broad physicochemical space.
亲脂性对许多决定游离药物暴露和药物效力的参数有主导作用。尽管如此，对大量药物数据的分析表明，亲脂性对剂量没有一致的定向影响。这可以根据亲脂性对药代动力学方程中单个参数值的影响的相互作用来合理化。我们认为，这削弱了针对亲脂性起主导作用的药物参数特定范围的策略的有效性。因此，我们的研究组织不再利用筛选低内在清除率以靶向高游离暴露率的常见方法。相反，我们主张通过优化控制剂量的关键参数比值来减少对亲脂性的偏见。我们相信，通过探索广泛的物理化学空间，这种方法可以提高药物发现的效率。
