Improving Solubility using X-ray crystal structure data

A recent publication from AstraZeneca provides a really interesting overview of the approach that they took to optimise the solubility of a series of GPR119 agonists. The initial lead compound 2 was only poorly soluble but, by obtaining small molecule x-ray structures of this and subsequent compounds, the AZ team were able to identify H-bonding networks within the crystal lattice and to target molecular features with the potential to disrupt these and other intermolecular interactions, thus lowering the melting point and increasing aqueous solubility. The paper describes this process in some detail and also highlights other key strategies that were used to progress from compound 2 through to 42, a clinical candidate for treating type II diabetes. The paper also serves to illustrate and build upon the concepts described in the review that we blogged previously.