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Design, synthesis and pre-clinical characterization of selective Factor D inhibitors targeting the alternative complement pathway

Karki, Rajeshri and Powers, James and Mainolfi, Nello and Anderson, Karen and Belanger, David and Liu, Donglei and Ji, Nan and Jendza, Keith and Gelin, Christine and Solovay, Catherine and Sweeney, Aengus and Delgado, Omar and Crowley, Maura and Liao, Sha-Mei and Argikar, Upendra and Flohr, Stefanie and La Bonte, Laura and Lorthiois, Edwige and Vulpetti, Anna and Cumin, Frederic and Brown, Ann and Adams, Christopher and Jaffee, Bruce and Mogi, Muneto (2019) Design, synthesis and pre-clinical characterization of selective Factor D inhibitors targeting the alternative complement pathway. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

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 (AMD), atypical hemolytic uremic syndrome (aHUS), membranoproliferative glomerulonephritis type II (MPGNII) and paroxysmal nocturnal hemoglobinuria (PNH). 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 (LPS)-induced AP activation model, as well as local ocular suppression in intravitreal injection-induced AP activation model in mice expressing human FD.

Item Type: Article
Date Deposited: 14 May 2019 00:45
Last Modified: 14 May 2019 00:45
URI: https://oak.novartis.com/id/eprint/38871

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