Discovery and structure–activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor

A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X7 receptor antagonist. Structure–activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X7 antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.