Physicochemical Properties and Safety Liabilities

Recent analyses demonstrating comparable mean values of lipophilicity, H-bond donors, and polar surface area between older (pre-1983) and newer (1983-2002) oral drugs suggest that these physicochemical attributes are fundamental characteristics of successful drugs. The noted increasing lipophilicity of compounds entering clinical development in recent years may have contributed to a commensurate higher rate of attrition [5,6]. 

Throughout the literature, there are many elegant studies linking physicochemical properties to in vitro outcomes however, it is often difficult to make a clear link to in vivo safety findings. There are a number of recent publications showing a correlation between physicochemical 

Of the physicochemical descriptors, lipophilicity (as described by clogP and Topological Polar Surface Area (TPSA) gave the strongest overall correlation to incidence of adverse in vivo outcomes, whether analyzed in terms of free or total drug threshold concentrations. In the case of free drug threshold analysis, a Random Forest statistical method indicated that there was a higher chance of a compound with TPSA 70 

Partial dependence on dogP free drug Partial dependence TPSA CCG free drug 

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