title: Synthesis and in vitro activity of N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine P2X(7) antagonists.
abstract: Synthesis and biological evaluation of a novel class of substituted N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine derivatives resulted in the identification of potent P2X(7) antagonists. These compounds were assayed for activity at both the human and rat P2X(7) receptors. On the benzyl moiety, a variety of functional groups were tolerated, including both electron-withdrawing and electron-donating substituents. Ortho-substitution on the benzyl group provided the greatest potency. The ortho-substituted analogs showed approximately 2.5-fold greater potency at human compared to rat P2X(7) receptors. Compounds 12 and 38 displayed hP2X(7)pIC(50)s>7.8 with less than 2-fold difference in potency at the rP2X(7).
authors.affiliation: Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Park, IL 60064-6101, United States. arturopm@sbcglobal.net
authors.forename: Arturo
authors.initials: A
authors.lastname: Perez-Medrano
authors.forename: Diana L
authors.initials: DL
authors.lastname: Donnelly-Roberts
authors.forename: Alan S
authors.initials: AS
authors.lastname: Florjancic
authors.forename: Derek W
authors.initials: DW
authors.lastname: Nelson
authors.forename: Tongmei
authors.initials: T
authors.lastname: Li
authors.forename: Marian T
authors.initials: MT
authors.lastname: Namovic
authors.forename: Sridhar
authors.initials: S
authors.lastname: Peddi
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: William A
authors.initials: WA
authors.lastname: Carroll
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D058920:Purinergic P2X Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000588:Amines; D058920:Purinergic P2X Receptor Antagonists; D013777:Tetrazoles; C045574:1H-tetrazole