Design and synthesis of next-generation C-C chemokine receptor type 5 antagonists.

The chemokine receptor CCR5 is a G protein-coupled receptor expressed on the surface of several types of immune cells. It acts as a mediator of the immune response and is therefore innately involved in several pathologies, including acute graft versus host disease, cancer and HIV. Maraviroc (MVC) is currently the only approved small-molecule CCR5 antagonist for HIV. Despite being approved and widely used, MVC comes with a black box warning for inducing potentially life-threatening hepatotoxicity. Furthermore, the drug has a less than ideal pharmacokinetic profile. This project focusses on the development of next-generation CCR5 antagonists, with more favourable pharmacokinetic properties, while maintaining the very high affinity observed with MVC. The development of CCR5 inhibitors has been mired in complications related to metabolic stability and associated therewith CYP inhibition and hepatotoxicity, as well as human Ether-à-go-go-Related Gene (hERG) potassium channel inhibition. Therefore, obtaining metabolically stable, orally available, non hERG-binding compounds is the goal for this project. In order to reach the goals set in this project, several complementary approaches will be used: optimization of MVC via structure guided drug design, molecular hybridization, intracellular CCR5 antagonists and virtual screening.