title: Identification of a Human Toll-Like Receptor (TLR) 8-Specific Agonist and a Functional Pan-TLR Inhibitor in 2-Aminoimidazoles.
abstract: Activation of human toll-like receptor-8 (TLR8), expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells, evokes a distinct cytokine profile which favors the development of Type 1 helper T cells. Part-structures of the 2-aminobenzimidazole scaffold were examined with a view to identifying structural requisites corresponding to the smallest possible fragment of the benzimidazole core that would allow for retention of TLR8-agonistic activity. TLR8-specific agonistic activity was retained in 1-pentyl-4-phenyl-1H-imidazol-2-amine. The crystal structure of this compound bound to the TLR8 ectodomain displayed binding interactions that are common to other TLR8 agonists. This compound showed markedly attenuated proinflammatory properties in ex vivo human blood models. SAR studies revealed that 4-(2-(benzyloxy)phenyl)-1-pentyl-1H-imidazol-2-amine inhibited TLR signaling in a variety of TLR reporter cell lines, as well as in pharmacologically relevant human blood model systems. A kinase screen of this compound showed relative specificity for calmodulin kinases.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.|Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Mallesh
authors.initials: M
authors.lastname: Beesu
authors.affiliation: Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Caruso
authors.affiliation: Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.|Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Alex C D
authors.initials: AC
authors.lastname: Salyer
authors.affiliation: Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.|Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Nijunj M
authors.initials: NM
authors.lastname: Shukla
authors.affiliation: Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Karishma K
authors.initials: KK
authors.lastname: Khetani
authors.affiliation: Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Smith
authors.affiliation: Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Fox
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo , Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanji
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo , Tokyo, Japan.
authors.forename: Umeharu
authors.initials: U
authors.lastname: Ohto
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo , Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Medicinal Chemistry, University of Kansas , Lawrence, Kansas 66047, United States.|Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D051200:Toll-Like Receptor 8 / Q000819:agonists*
chemical_list: C000611066:1-pentyl-4-phenyl-1H-imidazol-2-amine; C000611067:4-(2-(benzyloxy)phenyl)-1-pentyl-1H-imidazol-2-amine; D016207:Cytokines; D007093:Imidazoles; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; C014973:2-aminoimidazole; D017871:Calcium-Calmodulin-Dependent Protein Kinases