Small-molecule factor D inhibitors targeting the alternative complement pathway

Nat Chem Biol. 2016 Dec;12(12):1105-1110. doi: 10.1038/nchembio.2208. Epub 2016 Oct 24.

Abstract

Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH). Here we describe the identification of potent and selective small-molecule inhibitors of FD. These inhibitors efficiently block alternative pathway (AP) activation and prevent both C3 deposition onto, and lysis of, PNH erythrocytes. Their oral administration inhibited lipopolysaccharide-induced AP activation in FD-humanized mice. These data demonstrate the feasibility of inhibiting the AP with small-molecule antagonists and support the development of FD inhibitors for the treatment of complement-mediated diseases.

MeSH terms

  • Animals
  • Complement Factor D / antagonists & inhibitors*
  • Complement Factor D / metabolism
  • Complement Pathway, Alternative / drug effects*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Structure
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Small Molecule Libraries
  • Complement Factor D

Associated data

  • PubChem-Substance/318123738
  • PubChem-Substance/318123749
  • PubChem-Substance/318123754
  • PubChem-Substance/318123755
  • PubChem-Substance/318123756
  • PubChem-Substance/318123757
  • PubChem-Substance/318123758
  • PubChem-Substance/318123759
  • PubChem-Substance/318123760
  • PubChem-Substance/318123739
  • PubChem-Substance/318123740
  • PubChem-Substance/318123741
  • PubChem-Substance/318123742
  • PubChem-Substance/318123743
  • PubChem-Substance/318123744
  • PubChem-Substance/318123745
  • PubChem-Substance/318123746
  • PubChem-Substance/318123747
  • PubChem-Substance/318123748
  • PubChem-Substance/318123750
  • PubChem-Substance/318123751
  • PubChem-Substance/318123752
  • PubChem-Substance/318123753