Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo

J Med Chem. 2017 Jul 13;60(13):5717-5735. doi: 10.1021/acs.jmedchem.7b00425. Epub 2017 Jun 30.


The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.

MeSH terms

  • Administration, Oral
  • Animals
  • Atypical Hemolytic Uremic Syndrome / drug therapy
  • Atypical Hemolytic Uremic Syndrome / immunology
  • Complement Factor D / antagonists & inhibitors*
  • Complement Factor D / immunology
  • Complement Membrane Attack Complex / antagonists & inhibitors
  • Complement Membrane Attack Complex / immunology
  • Complement Pathway, Alternative / drug effects*
  • Female
  • Haplorhini
  • Humans
  • Macaca fascicularis
  • Macular Degeneration / drug therapy
  • Macular Degeneration / immunology
  • Male
  • Mice
  • Proline / administration & dosage
  • Proline / analogs & derivatives*
  • Proline / pharmacokinetics
  • Proline / pharmacology*


  • Complement Membrane Attack Complex
  • Proline
  • Complement Factor D