Synthesis and Structure-Activity Relationship Studies of New Bicyclic Compounds as P2X7 Receptor Antagonist

Abstract

P2X7 receptor (P2X7R), an adenosine triphosphate (ATP)-gated ion channel, has been reported as a key therapeutic target for many diseases such as inflammation, neuropathic pain, tumor, and central nervous system (CNS) disorder. Even though a few P2X7R antagonists have been developed until now, they failed in clinical trials. In this study, we report the development of bicyclic compound as new P2X7R antagonist. A benzothiophene derivative was previously selected as a hit compound and its P2X7R antagonistic activity has been optimized continuously. To further increase the P2X7R antagonistic activity of compound A, we explored the structure-activity relationship (SAR) study by using ethidium bromide (EtBr) uptake assay in human P2X7 receptor over-expressed human embryonic kidney (HEK) 293 cells. And then, we measured the functional inhibitory activity on P2X7R-mediated interleukin-1β (IL-1β) release by using IL-1β enzyme-linked immunosorbent assay (ELISA) in lipopolysaccharide (LPS)/interferon- γ (IFN-γ)/2’(3’)-O-(4-benzoylbenzoyl)-ATP (BzATP)-stimulated THP-1 cells. SAR study suggested that an isoquinoline sulfonyl group at region 1 (R1) position, a dimethylamine group at region 2 (R2) position, and an ethylpiperidine group connected by ether bond at region 3 (R3) position are important in P2X7R antagonistic activity. This new bicyclic compounds will be useful for further synthesis of P2X7R antagonists.