title: Structure-activity relationships and optimization of 3,5-dichloropyridine derivatives as novel P2X(7) receptor antagonists.
abstract: Screening of a library of chemical compounds showed that the dichloropyridine-based analogue 9 was a novel P2X(7) receptor antagonist. To optimize its activity, we assessed the structure-activity relationships (SAR) of 9, focusing on the hydrazide linker, the dichloropyridine skeleton, and the hydrophobic acyl (R(2)) group. We found that the hydrazide linker and the 3,5-disubstituted chlorides in the pyridine skeleton were critical for P2X(7) antagonistic activity and that the presence of hydrophobic polycycloalkyl groups at the R(2) position optimized antagonistic activity. In the EtBr uptake assay in hP2X(7)-expressing HEK293 cells, the optimized antagonists, 51 and 52, had IC(50) values of 4.9 and 13 nM, respectively. The antagonistic effects of 51 and 52 were paralleled by their ability to inhibit the release of the pro-inflammatory cytokine, IL-1β, by LPS/IFN-γ/BzATP stimulation of THP-1 cells (IC(50) = 1.3 and 9.2 nM, respectively). In addition, 52 strongly inhibited iNOS/COX-2 expression and NO production in THP-1 cells, further indicating that this compound blocks inflammatory signaling and suggesting that the dichloropyridine analogues may be useful in developing P2X(7) receptor targeted anti-inflammatory agents.
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors.forename: Won-Gil
authors.initials: WG
authors.lastname: Lee
authors.forename: So-Deok
authors.initials: SD
authors.lastname: Lee
authors.forename: Joong-Heui
authors.initials: JH
authors.lastname: Cho
authors.forename: Younghwan
authors.initials: Y
authors.lastname: Jung
authors.forename: Jeong-hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Tran T
authors.initials: TT
authors.lastname: Hien
authors.forename: Keon-Wook
authors.initials: KW
authors.lastname: Kang
authors.forename: Hyojin
authors.initials: H
authors.lastname: Ko
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D020382:Interleukin-18; D058920:Purinergic P2X Receptor Antagonists; D011724:Pyridazines; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human