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The discovery of 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-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

Mainolfi, Nello and Ehara, Takeru and Karki, Rajeshri and Anderson, Karen and Mac Sweeney, Aengus and Liao, Sha-Mei and Argikar, Upendra and Jendza, Keith and Zhang, Chun and Powers, James and Klosowski, Daniel and Crowley, Maura and Kawanami, Toshio and Ding, Jian and April, Myriam and Forster, Cornelia and Serrano-Wu, Michael and Capparelli, Michael and Ramqaj, Rrezarta and Solovay, Catherine and Cumin, Frederic and Smith, Thomas and Ferrara, Luciana and Lee, Wendy and Long, Debby and Prentiss, Melissa and De Erkenez, Andrea and Yang, Louis and Liu, Fang and Sellner, Holger and Sirockin, Finton and Valeur, Eric and Erbel, Paulus and Ramage, Paul and Gerhartz, Bernd and Ostermeier, Daniela and Schubart Wellensiek, Anna and Flohr, Stefanie and Gradoux, Nathalie and Feifel, Roland and Vogg, Barbara and Wiesmann, Christian and Maibaum, Juergen Klaus and Eder, Joerg and Sedrani, Richard and Harrison, Richard and Mogi, Muneto and Jaffee, Bruce and Adams, Christopher (2020) The discovery of 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-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. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

Abstract

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 pathway selective, orally bioavailable inhibitors has not been reported previously. Herein we describe our efforts to identify FB inhibitors by leveraging insights from several X-ray co-crystal structures. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse indications.

Item Type: Article
Keywords: Factor B, Alternative Pathway, Complement
Date Deposited: 05 Mar 2020 00:45
Last Modified: 05 Mar 2020 00:45
URI: https://oak.novartis.com/id/eprint/41161

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