Human Toll-like receptor 8-selective agonistic activities in 1-alkyl-1H-benzimidazol-2-amines

J Med Chem. 2014 Sep 11;57(17):7325-41. doi: 10.1021/jm500701q. Epub 2014 Aug 20.

Abstract

Toll-like receptor (TLR)-8 agonists strongly induce the production of T helper 1-polarizing cytokines and may therefore serve as promising candidate vaccine adjuvants, especially for the very young and the elderly. Earlier structure-based ligand design led to the identification of 3-pentyl-quinoline-2-amine as a novel, human TLR8-specific agonist. Comprehensive structure-activity relationships in ring-contracted 1-alkyl-1H-benzimidazol-2-amines were undertaken, and the best-in-class compound, 4-methyl-1-pentyl-1H-benzo[d]imidazol-2-amine, was found to be a pure TLR8 agonist, evoking strong proinflammatory cytokine and Type II interferon responses in human PBMCs, with no attendant CD69 upregulation in natural lymphocytic subsets. The 1-alkyl-1H-benzimidazol-2-amines represent a novel, alternate chemotype with pure TLR8-agonistic activities and will likely prove useful not only in understanding TLR8 signaling but also perhaps as a candidate vaccine adjuvant.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amines / chemistry
  • Amines / metabolism
  • Amines / pharmacology*
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Benzimidazoles / chemistry
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology*
  • Cells, Cultured
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Inflammation Mediators / metabolism
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / metabolism
  • Lectins, C-Type / metabolism
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / metabolism
  • Molecular Docking Simulation*
  • Molecular Structure
  • Structure-Activity Relationship
  • Toll-Like Receptor 8 / agonists*
  • Toll-Like Receptor 8 / chemistry
  • Toll-Like Receptor 8 / metabolism

Substances

  • 4-methyl-1-pentyl-1H-benzo(d)imidazol-2-amine
  • Amines
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Benzimidazoles
  • CD69 antigen
  • Cytokines
  • Inflammation Mediators
  • Lectins, C-Type
  • TLR8 protein, human
  • Toll-Like Receptor 8
  • Interferon-gamma