Chasing P2X7 Receptor Ligands for Cardiovascular Disease

Abstract

Cardiovascular disease (CVD) remains the leading cause of death in Australia, with atherosclerosis driving coronary artery disease (CAD), a severe form of CVD. The persistent inflammatory component of CAD necessitates novel therapies, as current treatments like low-dose colchicine rely on broad immunosuppression with inherent risks. P2X7R antagonists offer a promising alternative by selectively targeting CAD-specific inflammatory pathways, benefiting from extensive prior clinical evaluation and a favourable safety profile. This Thesis aimed to expand the structure-activity relationship (SAR) understanding of P2X7R antagonists and advance their preclinical development. Three compound series were investigated: PKT100 (trifluoroadamantyl benzamide), PKT200s (heterocyclic adamantyl cyanoguanidines), adamantyl–quinolinyl linkers, and the novel PKT400s (5-alkoxyalkylamine trifluoroadamantyl benzamides). The PKT200 chemotype was extensively explored, with ortho-halogenation emerging as a strategy to enhance potency. Adamantyl–quinolinyl pendant groups on various cores led to the discovery of a potent malononitrile analogue and insights into sulfonylguanidine and pyridazin-3-one scaffolds. A systematic preclinical assessment evaluated PKT100s, PKT200s, and PKT400s. While PKT200s exhibited exceptional potency, poor metabolic stability limited clinical potential. However, PKT400s demonstrated promising in vitro efficacy and pharmacokinetic (PK) profiles, outperforming PKT100 and the benchmark AZD9056. These findings contribute to the development of P2X7R antagonists with improved pharmacokinetic and pharmacodynamic properties, advancing therapies for CAD-associated inflammation.