Lipophilicity in drug discovery

Abstract

Importance of the field: The role of lipophilicity in determining the overall quality of candidate drug molecules is of paramount importance. Recent developments suggest that, as well as determining pre-clinical ADMET (absorption, distribution, metabolism, elimination and toxicology) properties, compounds of optimal lipophilicity might have increased chances of success in development.

Areas covered in this review: The review covers aspects of methods of prediction of lipophilicity in frequent use and describes the most relevant literature analyses linking individual ADMET parameters and more composite measures of overall compound ‘quality’ with lipophilicity.

What the reader will gain: The aim is to provide an overview of the relevant literature in an attempt to summarise where the optimum region of lipophilicity lies and to highlight which particular issues and risks might be expected when operating outside this region.

Take home message: The review of the data shows that this optimal space is defined by a narrow range of logD between ∼ 1 and 3. Some of the implications of this for medicinal chemistry optimisation are discussed.

Keywords::

• ADMET properties
• compound quality
• lead optimisation
• lipophilicity
• permeability
• pharamacokinetic properties
• physicochemical properties
• solubility
• toxicology

Acknowledgement

The author is grateful to C Johnstone and D McKerrecher for their thoughts and comments during the preparation of this manuscript.

Notes

This box summarises key points contained in the article.