title: Discovery of novel purine-based heterocyclic P2X7 receptor antagonists.
abstract: The pyridine core skeleton of the previously reported dichloropyridine-based potent hP2X7 receptor antagonist 5 (IC50 = 13 nM in hP2X7-expressing HEK293 cells) was modified with various heterocyclic scaffolds. Among the derivatives with quinoline, quinazoline, acridine, and purine scaffolds, the chloropurine-based analog 9o exhibited the most potent antagonistic activity, with an IC50 value of 176 ± 37 nM in an ethidium bromide uptake assay. In addition, 9o significantly inhibited IL-1β release in THP-1 cells stimulated with LPS/IFN-γ/BzATP (IC50 = 120 ± 15 nM). Although 9o was less active than the previous antagonist 5, 9o exhibited greatly improved metabolic stability in the in vitro evaluation (71.4% in human, 72.3% in mouse).
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, 261 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Seung-Hwa
authors.initials: SH
authors.lastname: Kwak
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
authors.forename: Won-Gil
authors.initials: WG
authors.lastname: Lee
authors.affiliation: Poly Oleffin Elastomer (POE) Project Team, LG Chemistry, 104-1, Moonji-dong, Yuseong-gu, Daejeon 305-738, Republic of Korea.
authors.forename: Yun-Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, 261 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: So-Deok
authors.initials: SD
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, 261 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, Republic of Korea; Department of Medical System Engineering (DMSE), Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea. Electronic address: yongchul@gist.ac.kr.
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, 261 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, Republic of Korea. Electronic address: kohyojin@gist.ac.kr.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Ko
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism; D011687:Purines / Q000737:chemistry*; D058486:Receptors, Purinergic P2X7 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006571:Heterocyclic Compounds; D058920:Purinergic P2X Receptor Antagonists; D011687:Purines; D058486:Receptors, Purinergic P2X7; C030985:purine
keywords: Antagonists; Ethidium bromide uptake; Human P2X(7)R; IL-1β; Metabolic stability