Mainolfi, Nello, Ehara, Takeru, Karki, Rajeshri, Anderson, Karen, Mac Sweeney, Aengus, Liao, Sha-Mei, Argikar, Upendra, Jendza, Keith, Zhang, Chun, Powers, James, Klosowski, Daniel, Crowley, Maura, Kawanami, Toshio, Ding, Jian, April, Myriam, Forster, Cornelia, Serrano-Wu, Michael, Capparelli, Michael, Ramqaj, Rrezarta, Solovay, Catherine, Cumin, Frederic, Smith, Thomas, Ferrara, Luciana, Lee, Wendy, Long, Debby, Prentiss, Melissa, De Erkenez, Andrea, Yang, Louis, Liu, Fang, Sellner, Holger, Sirockin, Finton, Valeur, Eric, Erbel, Paulus, Ramage, Paul, Gerhartz, Bernd, Ostermeier, Daniela, Schubart Wellensiek, Anna, Flohr, Stefanie, Gradoux, Nathalie, Feifel, Roland, Vogg, Barbara, Wiesmann, Christian, Maibaum, Juergen Klaus, Eder, Joerg, Sedrani, Richard, Harrison, Richard, Mogi, Muneto, 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