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.

The role of ligand efficiency metrics in drug discovery

“…7,12,13,14,15 This important observation implies that lipophilicity is a fundamental property impacting the progress of drug discovery programs and the developability of identified candidates. In contrast, it has been observed that the physicochemical properties of analogues in a chemical series, including molecular weight and lipophilicity, often increase during optimisation from hit to lead 23 and lead to candidate.…”

“…7,12,13,14,15 The median and mean molecular weight of approved drugs has risen by only around 50Da (15%) over the past 3 decades, whilst the median and mean molecular weight of synthesized experimental compounds has risen by over 100Da (30%). 16 In contrast, the molecules being published in the literature, 15 and patented by the pharmaceutical industry, 17 as well as those entering clinical development pipelines, 10 are more lipophilic, larger, and less three-dimensional 14,18 than approved oral drugs. Yet, compounds with higher molecular weight and higher lipophilicity face a higher probability of failure at each stage of clinical development.…”

Going further than Lipinski's rule in drug design

“…Molecules in pharmaceutical patents tended to be larger and more lipophilic than marketed drugs. In a 2011 paper, Leeson [7] again used marketed drugs and molecules from recent pharmaceutical patents to examine the differences among neutral, acidic and basic molecules. The authors found that while molecular mass increased over time for all ion classes, lipophilicity only increased for acidic and neutral molecules.…”

Discovery of a potent, orally available dual CysLT1 and CysLT2 antagonist with dicarboxylic acid

“…Therefore, there are many reports of the relationship between physical properties and permeability. [20][21][22][23][24][25][26][27][28][29][30] For example, Lipinski reported the relationship between the physical properties [molecular weight (MW), lipophilicity (C log P) and the number of hydrogen bond donors (HBDs) and acceptors (HBAs)] with permeability. Veber mentioned that polar surface area (PSA) and rotatable bonds (RotB) have correlation with permeability.…”