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

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.