Trends in Molecular Properties, Bioavailability, and Permeability across the Bayer Compound Collection

For oral drugs, medicinal chemists aim to design compounds with high oral bioavailability, of which permeability is a key determinant. Taking advantage of >2000 compounds tested in rat bioavailability studies and >20,000 compounds tested in Caco2 assays at Bayer, we have examined the molecular properties governing bioavailability and permeability. In addition to classical parameters such as logD and molecular weight, we also investigated the relationship between calculated pKa and permeability. We find that neutral compounds retain permeability up to a molecular weight limit of 700, while stronger acids and bases are restricted to weights of 400–500. We also investigate trends for common properties such as hydrogen bond donors and acceptors, polar surface area, aromatic ring count, and rotatable bonds, including compounds which exceed Lipinski’s rule of five (Ro5). These property–structure relationships are combined to provide design guidelines for bioavailable drugs in both traditional and “beyond rule of 5” (bRo5) chemical space.