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 anti-fibrotic 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 towards 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 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.

By Hartmut Beck, Tobias Thaler, Daniel Meibom, Mark Meininghaus, Hannah Joerissen, Lisa Dietz, Carsten Terjung, Michaela Bairlein, Clemens-Jeremias vonBuehler, Sonja Anlauf, Chantal Fuerstner, Timo Stellfeld, Dirk Schneider, Kersten Matthias Gericke, Thomas Buyck, Kai Dr. Lovis, Uwe muenster, Johanna Anlahr, Elisabeth Kersten, Guillaume Levilain, Virginia Marossek, and Raimund KastHTPK