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The influence of drug-like concepts on decision-making in medicinal chemistry

Nature Reviews Drug Discovery volume 6, pages 881–890 (2007)Cite this article

Key Points

  • Lipinski's 'rule of five' has been the leading measure of 'drug-likeness' for many companies since its publication 10 years ago. However, recent trends reveal that the physical properties of molecules that are currently being synthesized are significantly different from oral drugs that have been recently discovered or that are in clinical development.

  • In this article, physicochemical profiles of compounds from patent applications originating from AstraZeneca, GlaxoSmithKline, Merck and Co., and Pfizer are compared with the profiles of recently discovered oral drugs and compounds in development to analyse the specifics of these trends.

  • In general, for oral drugs approved since 1983, there has been an increase in molecular mass, O plus N atom count and OH plus NH count, whereas lipophilicity has remained relatively unchanged. We suggest that compound lipophilicity, as estimated by cLogP, is the most important molecular property, as it is changing less over time in launched oral drugs than other properties.

  • However, current medicinal chemistry efforts are producing compounds with higher molecular mass and cLogP than historical oral drugs, recent oral drugs and development compounds. The median patented compound has cLogP of 4.1 and molecular mass of 450 Da, whereas the most recent oral drugs, discovered since 1990, have median cLogP of 3.1 and molecular mass of 432 Da.

  • Although good pharmacokinetic profiles are important in drug development, toxicity is also crucial. It is shown that compound promiscuity is strongly related to lipophilicity. It is suggested that lipophilicity is the most important molecular property to consider for this aspect, as well as high potency, to reduce the risk of toxicity.

  • There is also a broad trend demonstrating that more extreme physical properties and therefore more complex molecules will have concomitantly increased risks to their developability, and thus decreased chances of success as they go through the development process.

  • Although there are many factors influencing the development of a compound, it is proposed that through careful selection of lead compounds and constant monitoring of physical properties (especially lipophilicity) during optimization, medicinal chemists could help alleviate attrition rates.

Abstract

The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity — the most important drug-like physical property — include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.

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Figure 1: Trends in cLogP and molecular mass in launched drugs.
Figure 2: Trends in drug approvals and their molecular mass.
Figure 3: Promiscuity analysis.
Figure 4: Trends in clogP and molecular mass in recently patented compounds from four pharmaceutical companies.
Figure 5: Overall trends in median cLogP and molecular mass in compounds from four pharmaceutical companies.
Figure 6: _target class trends in cLogP and molecular mass.
Figure 7: CCR5 as an example.

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Acknowledgements

We gratefully acknowledge numerous fruitful discussions on physical properties with AstraZeneca colleagues S. Boyer, D. Cheshire, A. Davis, J. Dixon, D. Lathbury, J. Li, J.-E. Nyström, G. Pairaudeau, M. Rolf (who provided BioPrint data), J. Steele, S. Teague and M. Wenlock (who helped to assemble the oral drugs database). J. Proudfoot (Boehringer Ingelheim Pharmaceuticals) very kindly provided his oral drug database.

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  1. AstraZeneca R&D Charnwood, Bakewell Road, LE15 5RH, Loughborough, UK

    Paul D. Leeson & Brian Springthorpe

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  1. Paul D. Leeson
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Correspondence to Paul D. Leeson.

Supplementary information

Supplementary information S1 (table)

The results of straight-line fits of mean property versus year for oral drugs launched from 1983-2006 (PDF 127 kb)

Supplementary information S2 (box)

Molecular weight (Mol wt) versus publication date for drug classes with common pharmacophores. (PDF 319 kb)

Supplementary information S3 (box)

Plots of promiscuity versus cLogP for Cerep Bioprint data, according to ionization type. (PDF 425 kb)

Supplementary information S4 (table)

Numbers of compounds or patents in _target classes by company and source (GVK Bio Patents, GVK Bio Compounds, Prous Integrity and 1983-2007 oral drugs (PDF 208 kb)

Supplementary information S5 (box)

Properties of oral drugs launched 1983-2007: cLogP. (PDF 5842 kb)

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SUPPLEMENTARY INFORMATION

S1 (table)

S2 (box)

S3 (box)

S4 (table)

S5 (box)

Glossary

LogP

Log of the octanol–water partition coefficient, which is a measure of a drug's lipophilicity. Defined as the ratio of un-ionized drug distributed between the octanol and water phases at equilibrium. Higher values imply greater lipophilicity.

Molecular mass

The molecular mass of a substance, frequently called molecular weight, is the mass of one molecule of that substance, and its units are the unified atomic mass unit (u) or Dalton (Da), which equals 1/12 the mass of one atom of carbon-12.

Polar surface area

(PSA). This is defined as the surface sum over all polar atoms, (usually oxygen and nitrogen), also including attached hydrogens.

Bioavailability

This is the fraction of an oral dose that reaches the systemic circulation.

Chemical space

This is the space spanned by all energetically stable stoichiometric combinations of electrons, atomic nuclei and topologies in molecules. Drug-like space may contain 1 × 1020 to 1 × 10200 molecules. All these molecules can never be made — to date 2.7 × 107 molecules have been reported.

Pharmacophore

The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological _target structure and to trigger (or to block) its biological response.

Phospholipidosis

Phospholipidosis is a lipid storage disorder in which excess phospholipids accumulate within cells. Drug-induced phospholipidosis occurs with many cationic amphiphilic drugs.

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Leeson, P., Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov 6, 881–890 (2007). https://doi.org/10.1038/nrd2445

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