Overcoming poor solubility is a significant issue in drug discovery. The most common solution is to replace carbon atoms with polar heteroatoms such as N and O or by attaching a solubilizing appendage. This approach can lead to other issues such as poor activity and PK or the increased risk for toxicity. However, there are more subtle structural changes which can be employed that lead to an increase in solubility. These include, excising hydrophobic groups which do not efficiently contribute to binding, modifying stereo- and regiochemistry, increasing or decreasing the degree of unsaturation or adding small hydrophobic groups such as fluorine or methyl.