Discovery of 4-((2 <i>S</i> ,4 <i>S</i> )-4-Ethoxy-1-((5-methoxy-7-methyl-1 <i>H</i> -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
Nello Mainolfi, Takeru Ehara, Rajeshri G. Karki, Karen Anderson, A. Mac Sweeney, Sha-Mei Liao, Upendra A. Argikar, Keith Jendza, Chun Zhang, James J. Powers, Daniel W. Klosowski, Maura Crowley, Toshio Kawanami, Jian Ding, Myriam April, Cornelia J. Forster, Michael H. Serrano‐Wu, Michael Capparelli, R. Ramqaj, Catherine Solovay, Frédéric Cumin, Thomas M. Smith, Luciana Ferrara, Wendy Lee, Debby Long, Melissa Prentiss, A. De Erkenez, Louis Yang, Fang Liu, Holger Sellner, Finton Sirockin, Eric Valeur, P. Erbel, Daniela Ostermeier, Paul Ramage, Bernd Gerhartz, Anna Schubart, Stefanie Flohr, Nathalie Gradoux, Roland Feifel, Barbara Vogg, Christian Wiesmann, Jürgen Maibaum, Jörg Eder, Richard Sedrani, R. A. Harrison, Muneto Mogi, Bruce Jaffee, Christopher M. Adams
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, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.