Impact of ion class and time on oral drug molecular properties

Abstract

Using databases of oral drugs and recent compounds from the patents of major pharmaceutical companies, trends in molecular properties over time are identified. It is shown that the physical property profiles of oral drugs are not absolute, but depend on both ion class and the time of the drug invention. Properties examined include lipophilicity, molecular weight, hydrogen bond donors and acceptors, polar surface area, aromaticity, chirality and tetrahedral (sp3) carbon atom count. Lipophilicity is increasing over time in oral drugs that are neutral or acidic, but not in basic drugs, and has been converging in all ion classes towards a common constant range since the 1960s. In contrast, molecular weight is increasing over time in all ion classes. Hydrogen bond donors (OH + NH group count) are stable over time but hydrogen bond acceptors (O + N atom count) are increasing over time. It is shown that measures using sp3 atom and aromatic atom counts are inversely related and a new parameter, Ar atom count – sp3 atom count (Ar-sp3), describing shape or aromatic/aliphatic balance, is introduced. Ar-sp3 is constant over time in oral drugs, but is higher in patented compounds, independently of molecular weight and lipophilicity. The ion classes in patent compounds occupy distinct molecular weight/lipophilicity/shape chemical space. These properties are significantly increased versus oral drugs, with the exception of the most recently discovered acidic drugs, and occur in most, but not all target classes. While ceilings for lipophilicity in acids and neutral compounds may not have been reached, the design of potential drug molecules with reduced ADMET risk is indicated by a seeking a better balance between lipophilicity, 3-dimensionality and aromaticity.