Identification of a Human Toll-Like Receptor (TLR) 8-Specific Agonist and a Functional Pan-TLR Inhibitor in 2-Aminoimidazoles
| Autor: | Toshiyuki Shimizu, Karishma K. Khetani, Luke J. Smith, Umeharu Ohto, Nijunj M. Shukla, Sunil A. David, Giuseppe Caruso, Lauren M. Fox, H. Tanji, Mallesh Beesu, Alex C. D. Salyer |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class Monocytes Proinflammatory cytokine Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Drug Discovery medicine Humans Structure–activity relationship Protein Kinase Inhibitors Cells Cultured Toll-like receptor Chemistry Imidazoles NF-kappa B Cell biology 030104 developmental biology Biochemistry Ectodomain Toll-Like Receptor 8 Cell culture 030220 oncology & carcinogenesis Calcium-Calmodulin-Dependent Protein Kinases Leukocytes Mononuclear Cytokines Molecular Medicine Signal transduction Ex vivo Signal Transduction |
| Zdroj: | Journal of Medicinal Chemistry. 59:3311-3330 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b00023 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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