Potent and Selective Human Prostaglandin F (FP) Receptor Antagonist (BAY-6672) for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)
In: Journal of Medicinal Chemistry, Jg. 63 (2020-10-22), Heft 20, S. 11639-11662
serialPeriodical
Zugriff:
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 Frelfrom 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 vivoefficacy in a preclinical animal model of lung fibrosis, thus paving the way for a new treatment option in IPF.
Titel: |
Potent and Selective Human Prostaglandin F (FP) Receptor Antagonist (BAY-6672) for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)
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Autor/in / Beteiligte Person: | Beck, Hartmut ; Thaler, Tobias ; Meibom, Daniel ; Meininghaus, Mark ; Jörißen, Hannah ; Dietz, Lisa ; Terjung, Carsten ; Bairlein, Michaela ; von Bühler, Clemens-Jeremias ; Anlauf, Sonja ; Fürstner, Chantal ; Stellfeld, Timo ; Schneider, Dirk ; Gericke, Kersten M. ; Buyck, Thomas ; Lovis, Kai ; Münster, Uwe ; Anlahr, Johanna ; Kersten, Elisabeth ; Levilain, Guillaume ; Marossek, Virginia ; Kast, Raimund |
Zeitschrift: | Journal of Medicinal Chemistry, Jg. 63 (2020-10-22), Heft 20, S. 11639-11662 |
Veröffentlichung: | 2020 |
Medientyp: | serialPeriodical |
ISSN: | 0022-2623 (print) ; 1520-4804 (print) |
DOI: | 10.1021/acs.jmedchem.0c00834 |
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