Time-Related Differences in the Physical Property Profiles of Oral Drugs

Comparisons of the calculated physicochemical properties of oral drugs launched prior to 1983
(864 drugs) and between 1983 and 2002 (329 drugs) show that mean values of lipophilicity,
percent polar surface area and H-bond donor count are the same, suggesting that these are
the most important oral druglike physical properties. In contrast, mean values of molecular
weight and the numbers of O + N atoms, H-bond acceptors, and rotatable bonds and rings
have increased in 1983−2002 drugs (by 13−29%). Analysis of the 1983−2002 oral drugs by
therapy area shows that antiinfectives and nervous system drugs have the most extreme
physical property profiles. Cardiovascular drugs show increasing molecular weight with year
of publication, primarily a consequence of focusing on clinically proven mechanisms, with limited
chemical diversity. Drug classes other than antiinfectives show comparable distributions of
lipophilicity, suggesting that this property in oral drugs is important irrespective of the drug's
target. The results suggest that the balance between polar and nonpolar drug properties is an
important, unchanging feature of oral drug molecules.