Molecular Hybridization of Clinically Relevant P2X7 Antagonists

The P2X7 receptor plays a pivotal role in the development of neurodegenerative disease states, yet no therapies targeting this receptor have reached the market to date. This work utilized a hybridization approach to combine clinically relevant antagonists AZD‐9056 and JNJ‐54175446 to discover new P2X7 antagonists. Here, we report the synthesis and in vitro and in silico evaluation of a library of 22 compounds to explore new chemical space around these clinically validated molecules. This study emphasizes the value of molecular hybridization in drug discovery and provides the basis for future P2X7 receptor antagonist development.