2. Academic Validation
  3. Potent and Selective Human Prostaglandin F (FP) Receptor Antagonist (BAY-6672) for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

Potent and Selective Human Prostaglandin F (FP) Receptor Antagonist (BAY-6672) for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

  • J Med Chem. 2020 Oct 22;63(20):11639-11662. doi: 10.1021/acs.jmedchem.0c00834.
Hartmut Beck 1,  Tobias Thaler 1,  Daniel Meibom 1,  Mark Meininghaus 1,  Hannah Jörißen 1,  Lisa Dietz 1,  Carsten Terjung 1,  Michaela Bairlein 1,  Clemens-Jeremias von Bühler 1,  Sonja Anlauf 1,  Chantal Fürstner 1,  Timo Stellfeld 2,  Dirk Schneider 1,  Kersten M Gericke 1,  Thomas Buyck 1,  Kai Lovis 1,  Uwe Münster 1,  Johanna Anlahr 1,  Elisabeth Kersten 1,  Guillaume Levilain 1,  Virginia Marossek 1,  Raimund Kast 1
Affiliations

Affiliations

  • 1 Research & Development, Pharmaceuticals, Bayer AG, 42096 Wuppertal, Germany.
  • 2 Research & Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany.
PMID: 32969660 DOI: 10.1021/acs.jmedchem.0c00834
Abstract

Idiopathic pulmonary fibrosis (IPF) is a rare and devastating chronic lung disease of unknown etiology. Despite the approved treatment options nintedanib and pirfenidone, the medical need for a safe and well-tolerated antifibrotic treatment of IPF remains high. The human prostaglandin F receptor (hFP-R) is widely expressed in the lung tissue and constitutes an attractive target for the treatment of fibrotic lung diseases. Herein, we present our research toward novel quinoline-based hFP-R antagonists, including synthesis and detailed structure-activity relationship (SAR). Starting from a high-throughput screening (HTS) hit of our corporate compound library, multiple parameter improvements-including increase of the relative oral bioavailability Frel from 3 to ≥100%-led to a highly potent and selective hFP-R antagonist with complete oral absorption from suspension. BAY-6672 (46) represents-to the best of our knowledge-the first reported FP-R antagonist to demonstrate in vivo efficacy in a preclinical animal model of lung fibrosis, thus paving the way for a new treatment option in IPF.

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