Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists

The P2X7 receptor (P2X7R) stands out among the purinergic receptors due to its strong involvement in the regulation of tumor growth and metastasis formation as well as in innate immune responses and afferent signal transmission. Numerous studies have pointed out the beneficial effects of P2X7R antagonism for the treatment of a variety of cancer types, inflammatory diseases, and chronic pain. Herein we describe the development of novel P2X7R antagonists, incorporating piperazine squaric diamides as a central element. Besides improving the antagonists' potency from pIC(50) values of 5.7-7.6, ADME properties (logD(7.4) value, plasma protein binding, in vitro metabolic stability) of the generated compounds were investigated and optimized to provide novel P2X7R antagonists with drug-like properties. Furthermore, docking studies revealed the antagonists binding to the allosteric binding pocket in two distinct binding poses, depending on the substitution of the central piperazine moiety. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

The P2X7 receptor plays a crucial role in regulating tumor growth and immune responses, with its antagonists showing promising therapeutic effects in cancer, inflammatory diseases, and chronic pain. Novel P2X7R antagonists incorporating piperazine squaric diamides have been developed with improved potency and drug-like properties through optimization of ADME characteristics. Docking studies revealed the antagonists binding to allosteric pockets in two distinct poses, depending on the substitution of the central piperazine moiety.