As an optimization strategy, the flexible structure of KN-62, a known P2X7 receptor antagonist, was converted into conformationally constrained derivatives using pyrimidine-2,4-dione as the core skeleton. Various modifications at the 4-position of the piperazine moiety of the new lead compound were performed to improve P2X7 receptor antagonistic activities, which were evaluated in HEK293 cells stably expressing the human P2X7 receptor (EtBr uptake assay) and in THP-1 cells (IL-1β ELISA assay). According to the results, polycycloalkyl acyl or di-halogenated benzoyl substituents were much more favorable than the original phenyl group of KN-62. Among these compounds, the trifluoromethyl-chloro benzoyl derivative 18 m and adamantyl carbonyl derivatives 19 g-19 i and 19k showed potent antagonistic effects, with IC50 values ranging from 10 to 30 nM. In addition, the in vitro adsorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of 18 m was determined to be in acceptable ranges in terms of metabolic stability and cytotoxicity. These results suggest that pyrimidine-2,4-dione derivatives may be promising novel P2X7 receptor antagonists for the development of anti-inflammatory drugs.
Keywords: Antagonists; IL-1β; Inflammation; KN-62; P2X(7) receptor; Structure–activity relationships.
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