2. Academic Validation
  3. Discovery of 4-((2 S,4 S)-4-Ethoxy-1-((5-methoxy-7-methyl-1 H-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

Discovery of 4-((2 S,4 S)-4-Ethoxy-1-((5-methoxy-7-methyl-1 H-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

  • J Med Chem. 2020 Jun 11;63(11):5697-5722. doi: 10.1021/acs.jmedchem.9b01870.
Nello Mainolfi 1,  Takeru Ehara 1,  Rajeshri G Karki 1,  Karen Anderson 1,  Aengus Mac Sweeney 2,  Sha-Mei Liao 1,  Upendra A Argikar 1,  Keith Jendza 1,  Chun Zhang 1,  James Powers 1,  Daniel W Klosowski 1,  Maura Crowley 1,  Toshio Kawanami 1,  Jian Ding 1,  Myriam April 1,  Cornelia Forster 1,  Michael Serrano-Wu 1,  Michael Capparelli 1,  Rrezarta Ramqaj 2,  Catherine Solovay 1,  Frederic Cumin 2,  Thomas M Smith 1,  Luciana Ferrara 1,  Wendy Lee 1,  Debby Long 1,  Melissa Prentiss 1,  Andrea De Erkenez 1,  Louis Yang 1,  Fang Liu 1,  Holger Sellner 2,  Finton Sirockin 2,  Eric Valeur 2,  Paulus Erbel 2,  Daniela Ostermeier 2,  Paul Ramage 2,  Bernd Gerhartz 2,  Anna Schubart 2,  Stefanie Flohr 2,  Nathalie Gradoux 2,  Roland Feifel 2,  Barbara Vogg 2,  Christian Wiesmann 2,  Jürgen Maibaum 2,  Jörg Eder 2,  Richard Sedrani 2,  Richard A Harrison 2,  Muneto Mogi 1,  Bruce D Jaffee 1,  Christopher M Adams 1
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
  • 2 Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
PMID: 32073845 DOI: 10.1021/acs.jmedchem.9b01870
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.

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