Yukawa Tomoya, Naven Russell
Drug Safety Research and Evaluation, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 35 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
Drug Safety Research and Evaluation, Pharmaceutical Research Division, Takeda Pharmaceuticals International Company Limited, 9625 Towne Centre Drive, San Diego, California 92121, United States.
ACS Med Chem Lett. 2020 Jan 29;11(2):203-209. doi: 10.1021/acsmedchemlett.9b00536. eCollection 2020 Feb 13.
The role that physicochemical properties play toward increasing the likelihood of toxicity findings in studies has been well reported, albeit sometimes with different conclusions. We decided to understand the role that physicochemical properties play toward the prediction of toxicological outcomes for Takeda chemistry using 284 internal compounds. In support of the previously reported "3/75 rule", reducing lipophilicity of molecules decreases toxicity odds noticeably; however, we also found that the trend of toxicity odds is different between compounds classified by their ionization state. For basic molecules, the odds of toxicity outcomes were significantly impacted by both lipophilicity and polar surface area, whereas neutral molecules were impacted less so. Through an analysis of several project-related compounds, we herein demonstrate that the utilization of the 3/75 rule coupled with consideration of ionization state is a rational strategy for medicinal chemistry design of safer drugs.
物理化学性质在研究中对增加毒性发现可能性所起的作用已有充分报道，尽管有时会得出不同结论。我们决定利用284种内部化合物来了解物理化学性质对武田化学毒理学结果预测所起的作用。支持先前报道的“3/75规则”，降低分子的亲脂性会显著降低毒性几率；然而，我们还发现，根据电离状态分类的化合物之间毒性几率的趋势有所不同。对于碱性分子，毒性结果的几率受亲脂性和极性表面积的显著影响，而中性分子受影响较小。通过对几种与项目相关的化合物的分析，我们在此证明，结合电离状态考虑使用3/75规则是药物化学设计更安全药物的合理策略。
