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

Abstract

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.

Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain

“…A wealth of scholarship exists about the differences in the physical chemical properties of CNS versus nonCNS drugs (21)(22)(23) and in fact, a number of computed properties vary signifi cantly between the two groups. Compounds possessing molecular parameters outside of the "ideal" ranges for CNS drugs tend to either have poor passive diffusion through cell membranes or to be substrates for MDR1 mediated effl ux.…”

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.…”

Conformational Analysis, Substituent Effect and Structure Activity Relationships of 16-Membered Macrodiolides

“…We will continue this work in the future by a quantitative calculation. [60] A quantitative characterization based on computed physicochemical property profiles such as Polarizability [29], Partition Coefficient (log P) [30][31][32][33], Hydration Energy [34][35][36], Molecular Volume [37], Molecular Surface and Molecular Mass [38] has been conducted. The physicochemical parameters used in the study are described below.…”