2. Academic Validation
  3. Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway

Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway

  • J Med Chem. 2019 May 9;62(9):4656-4668. doi: 10.1021/acs.jmedchem.9b00271.
Rajeshri G Karki 1,  James Powers 1,  Nello Mainolfi 1,  Karen Anderson 1,  David B Belanger 1,  Donglei Liu 1,  Nan Ji 1,  Keith Jendza 1,  Christine F Gelin 1,  Aengus Mac Sweeney 2,  Catherine Solovay 1,  Omar Delgado 1,  Maura Crowley 1,  Sha-Mei Liao 1,  Upendra A Argikar 1,  Stefanie Flohr 2,  Laura R La Bonte 1,  Edwige L Lorthiois 2,  Anna Vulpetti 2,  Ann Brown 1,  Debby Long 1,  Melissa Prentiss 1,  Nathalie Gradoux 2,  Andrea de Erkenez 1,  Frederic Cumin 2,  Christopher Adams 1,  Bruce Jaffee 1,  Muneto Mogi 1
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research , Cambridge , Massachusetts 02139 , United States.
  • 2 Novartis Institutes for BioMedical Research , Novartis Campus , CH-4056 Basel , Switzerland.
PMID: 30995036 DOI: 10.1021/acs.jmedchem.9b00271
Abstract

Complement Factor D (FD), a highly specific S1 serine Protease, plays a central role in the amplification of the alternative complement pathway (AP) of the innate immune system. Dysregulation of AP activity predisposes individuals to diverse disorders such as age-related macular degeneration, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II, and paroxysmal nocturnal hemoglobinuria. Previously, we have reported the screening efforts and identification of reversible benzylamine-based FD inhibitors (1 and 2) binding to the open active conformation of FD. In continuation of our drug discovery program, we designed compounds applying structure-based approaches to improve interactions with FD and gain selectivity against S1 serine proteases. We report herein the design, synthesis, and medicinal chemistry optimization of the benzylamine series culminating in the discovery of 12, an orally bioavailable and selective FD inhibitor. 12 demonstrated systemic suppression of AP activation in a lipopolysaccharide-induced AP activation model as well as local ocular suppression in intravitreal injection-induced AP activation model in mice expressing human FD.

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