Utility of Physicochemical Properties for the Prediction of Toxicological Outcomes: Takeda Perspective

The role that physicochemical properties play toward increasing the likelihood of toxicity findings in in vivo studies has been well reported, albeit sometimes with different conclusions. We decided to understand the role that physicochemical properties play toward the prediction of in vivo 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 in vivo 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.