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

Journal of medicinal chemistry 2020 Oct 22

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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.

Citation

Hartmut Beck, Tobias Thaler, Daniel Meibom, Mark Meininghaus, Hannah Jörißen, Lisa Dietz, Carsten Terjung, Michaela Bairlein, Clemens-Jeremias von Bühler, Sonja Anlauf, Chantal Fürstner, Timo Stellfeld, Dirk Schneider, Kersten M Gericke, Thomas Buyck, Kai Lovis, Uwe Münster, Johanna Anlahr, Elisabeth Kersten, Guillaume Levilain, Virginia Marossek, Raimund Kast. Potent and Selective Human Prostaglandin F (FP) Receptor Antagonist (BAY-6672) for the Treatment of Idiopathic Pulmonary Fibrosis (IPF). Journal of medicinal chemistry. 2020 Oct 22;63(20):11639-11662