Discovery of 4-((2 S,4 S)-4-Ethoxy-1-((5-methoxy-7-methyl-1 H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases

J Med Chem. 2020 Jun 11;63(11):5697-5722. doi: 10.1021/acs.jmedchem.9b01870. Epub 2020 Feb 19.


The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atypical Hemolytic Uremic Syndrome / metabolism
  • Atypical Hemolytic Uremic Syndrome / pathology
  • Benzoic Acid / chemistry*
  • Benzoic Acid / metabolism
  • Benzoic Acid / pharmacokinetics
  • Binding Sites
  • Catalytic Domain
  • Complement Factor B / antagonists & inhibitors*
  • Complement Factor B / metabolism
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacokinetics
  • Inhibitory Concentration 50
  • Macular Degeneration / metabolism
  • Macular Degeneration / pathology
  • Molecular Dynamics Simulation
  • Structure-Activity Relationship


  • Indoles
  • Benzoic Acid
  • Complement Factor B