Velsecorat

Process development activities required to develop a robust and scalable synthetic route to AZD7594 are disclosed.Included in this paper is the rational for the selection of a palladium mediated Buchwald-Hartwig coupling to form a key C-N bond.Reaction optimization and understanding were performed in order to minimize impurity formation and to develop a robust control strategy.The optimized synthetic sequence was used to manufacture 220 kg of AZD7594 for clin. trials.

The glucocorticoid receptor (GR) is a ligand-activated transcription factor that binds DNA and assembles co-regulator complexes to regulate gene transcription. GR agonists are widely prescribed to people with inflammatory and autoimmune diseases. Here we present high-resolution, multidomain structures of GR in complex with ligand, DNA and co-regulator peptide. The structures reveal how the receptor forms an asymmetric dimer on the DNA and provide a detailed view of the domain interactions within and across the two monomers. Hydrogen-deuterium exchange and DNA-binding experiments demonstrate that ligand-dependent structural changes are communicated across the different domains in the full-length receptor. This study demonstrates how GR forms a distinct architecture on DNA and how signal transmission can be modulated by the ligand pharmacophore, provides a platform to build a new level of understanding of how receptor modifications can drive disease progression and offers key insight for future drug design.