Phosphoinositide 3-kinases (PI3Ks) are lipid kinases that play a key role in the control of a wide number of cellular functions including metabolism, cell growth and motility.  In terms of tissue distribution, PI3Ka and � are ubiquitously expressed whereas PI3Kd and ? are mainly expressed in leukocytes.  In conjunction with mouse genetic studies, these enzymes are viewed as promising targets for the treatment of a number of inflammatory and oncologic diseases.  Due to the high levels of expression of PI3Ka and � in various tissues along with a different signaling route for PI3K? through GPCRs, a highly selective PI3Kd compound was desired.  Through SAR and Structure-based design, analog 20  was identified to increase biochemical selectivity, potency and solubility of this series that resulted in superior cellular selectivity with acceptable in vivo PK properties.  Compound 20  was also found to be efficacious in vivo, which included evaluation in a keyhole limpet hemocyanin (KLH) study and a pAKT inflammation study.  Therefore, this class of compounds should show great promise as a therapeutic for numerous inflammation disease states.

SAR and rational design of novel, selective PI3Kδ inhibitors

245th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.