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
posted on 2020-02-19, 19:08authored byNello Mainolfi, Takeru Ehara, Rajeshri G. Karki, Karen Anderson, Aengus Mac Sweeney, Sha-Mei Liao, Upendra A. Argikar, Keith Jendza, Chun Zhang, James Powers, Daniel W. Klosowski, Maura Crowley, Toshio Kawanami, Jian Ding, Myriam April, Cornelia Forster, Michael Serrano-Wu, Michael Capparelli, Rrezarta Ramqaj, Catherine Solovay, Frederic Cumin, Thomas M. Smith, Luciana Ferrara, Wendy Lee, Debby Long, Melissa Prentiss, Andrea De Erkenez, Louis Yang, Fang Liu, Holger Sellner, Finton Sirockin, Eric Valeur, Paulus 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, Richard A. Harrison, Muneto Mogi, Bruce D. Jaffee, Christopher M. Adams
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.