Lipp, Ralph; American Pharmaceutical Review (2013), 16(3), 10, 12, 14-16.
There have been many recent publications highlighting the disturbing trend in current pharmaceutical development pipelines towards molecules with high lipophilicity, high molecular weight and other parameters outside of the traditional Lipinski values. These molecules have a significantly reduced chance of progressing along the path towards the market. Interestingly little mention is made in these papers of aqueous solubility.
Figure 1 shows the percentage of current pipeline drugs and how there are distributed amongst the biopharmaceutical classification groups compared with currently marketed drugs. Disturbingly more than 80% of current pipeline drugs are classified as having low aqueous solubility compared with less than 40% for marketed drugs.
In his article the author explains the issue that this low solubility poses with regard to achieving oral bioavailability and highlights the need for new and improved, advanced oral drug delivery technologies which can enhance bioavailability.
This is indeed the case for molecules in todays pharmaceutical pipeline, but may not solve all of the problems for example safety assessment studies require drugs to be administered at high doses and to achieve high blood concentrations, this is not always possible with poorly soluble drugs even when formulation technologies have been employed, and, in certain cases, has resulted in development being halted.
Todays pipeline will, as the author indicates, need technological advances to aid its development, this is likely however to make development longer and more costly.
As suggested by many authors in recent articles which discuss physical chemistry properties, medicinal chemists need to think more carefully about physical properties when designing new compounds. Reduction in lipophilicity and aromatic ring count will result in compounds with improved physical properties which will not only have a greater chance of success in development, the process will be cheaper and more efficient as will not require complex formulation techniques.