How important is solubility? Well, if like me you enjoy a sugar in your coffee, the answer is “pretty important”. In order for the sugar to be able to reach my taste-buds in adequate concentration to achieve that welcome sensation of sweetness, the sugar needs to be soluble enough in hot milky water. So too, for a successful drug, which, like the sugar, must dissolve and then reach a site of action in sufficient quantity to elicit a pharmacological response. Solubility is taken very seriously by pharmaceutical scientists.
The problem for the unfortunate drug development chemist is that if they are given an Active Pharmaceutical Ingredient (API) with less than optimum solubility properties (in other words “Brick Dust”) , then great ingenuity is needed to create a viable formulation. Failure to do so can be very costly and does not promote harmonious relations between the Discovery and Development groups!
Solubility has therefore become a consideration very early on in the drug design process and solubility assays will generally be performed on all important lead compounds. Solubility is a function not only of chemical structure but also of crystal form. This is well understood by the drug development community but perhaps less well so by their drug discovery counterparts. In principle, information could be derived from the crystal form of a poorly-soluble lead molecule which could lead to drug candidates with improved solubility. But up till now such rational design for improved solubility has rarely been incorporated into the drug discovery process.
In this light a recent publication by scientists at AstraZeneca , makes very welcome reading (Scott et al, J. Med. Chem., 2012, 55, 5361-5379, doi: 10.1021/jm300310c). Small molecule crystal structures were obtained of some early, poorly-soluble leads in a programme to design G Protein Coupled Receptor 119 agonists . Crystal structure stabilising interactions were then identified through a comparative analysis of similar chemistry in the Cambridge Structural Database (CSD). Bioisosteric replacements were then introduced that could not make these stabilising interactions. The new designs retained good activity and were found to be much more soluble.
The value of small molecule crystal information to ensure good molecular geometry is already well recognised by many drug discovery chemist and modellers. This paper illustrates that they can use the same information to streamline the path to a clinical candidate keeping their development colleagues happy and cheerful at the same time.
If you’d like to examine the crystal structures described in this paper they are accessible via WebCSD, the place to go for recently published CSD structures (contact if you need further details on accessing WebCSD). The structures have the refcodes SEMPAD (compound 2), SEMPEH (compound 12) and SEMNUV (compound 27).