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
  • 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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