Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway
| Autor: | Anna Vulpetti, Upendra A. Argikar, Stefanie Flohr, Aengus Mac Sweeney, Melissa Prentiss, Edwige Lorthiois, Karen Anderson, David B. Belanger, Sha-Mei Liao, Nan Ji, Christopher M. Adams, Frederic Cumin, Andrea De Erkenez, Nathalie Gradoux, Muneto Mogi, Donglei Liu, Maura Crowley, Keith Jendza, Debby Long, Nello Mainolfi, Catherine Solovay, Ann Brown, Laura R. La Bonte, Rajeshri Ganesh Karki, Omar Delgado, Powers James J, Bruce D Jaffee, Christine F. Gelin |
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| Rok vydání: | 2019 |
| Předmět: |
Benzylamines
Serine Proteinase Inhibitors Protein Conformation Complement Pathway Alternative Mice Transgenic 01 natural sciences 03 medical and health sciences Dogs Complement Factor D Drug Discovery Hydrolase Animals Humans 030304 developmental biology Serine protease 0303 health sciences Innate immune system Binding Sites biology Chemistry 0104 chemical sciences Cell biology Rats Mice Inbred C57BL Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Design synthesis Drug Design Alternative complement pathway biology.protein Molecular Medicine Factor D Medical science |
| Zdroj: | Journal of medicinal chemistry. 62(9) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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