title: Small-molecule factor D inhibitors targeting the alternative complement pathway.
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.
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Jürgen
authors: J
authors: Maibaum
authors: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors: Sha-Mei
authors: SM
authors: Liao
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Anna
authors: A
authors: Vulpetti
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Nils
authors: N
authors: Ostermann
authors: Evonik Japan Co., Shinjuku-ku, Tokyo, Japan.
authors: Stefan
authors: S
authors: Randl
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Simon
authors: S
authors: Rüdisser
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Edwige
authors: E
authors: Lorthiois
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Paul
authors: P
authors: Erbel
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Bernd
authors: B
authors: Kinzel
authors: Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors: Fabrice A
authors: FA
authors: Kolb
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Samuel
authors: S
authors: Barbieri
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Julia
authors: J
authors: Wagner
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Corinne
authors: C
authors: Durand
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Kamal
authors: K
authors: Fettis
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Solene
authors: S
authors: Dussauge
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Nicola
authors: N
authors: Hughes
authors: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors: Omar
authors: O
authors: Delgado
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Ulrich
authors: U
authors: Hommel
authors: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors: Ty
authors: T
authors: Gould
authors: Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors: Aengus
authors: http://orcid.org/0000-0001-7250-9541
authors: A
authors: Mac Sweeney
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Bernd
authors: B
authors: Gerhartz
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Frederic
authors: F
authors: Cumin
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Stefanie
authors: S
authors: Flohr
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Anna
authors: A
authors: Schubart
authors: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors: Bruce
authors: B
authors: Jaffee
authors: Institute of Infection and Immunity, School of Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff, UK.
authors: Richard
authors: R
authors: Harrison
authors: University of Naples, Department of Clinical Medicine and Surgery, Division of Hematology, Naples, Italy.
authors: Antonio Maria
authors: AM
authors: Risitano
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.
authors: Jörg
authors: J
authors: Eder
authors: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors: Karen
authors: K
authors: Anderson
mesh_terms: D000818:Animals; D011416:Complement Factor D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D054852:Small Molecule Libraries; D011416:Complement Factor D