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 F_rel 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.

中文翻译：

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一种有效的选择性人前列腺素F（FP）受体拮抗剂（BAY-6672），用于治疗特发性肺纤维化（IPF）。

特发性肺纤维化（IPF）是一种病因不明的罕见且具有毁灭性的慢性肺部疾病。尽管批准了nintedanib和pirfenidone的治疗选择，但对IPF的安全耐受性良​​好的抗纤维化治疗的医疗需求仍然很高。人前列腺素F受体（hFP-R）在肺组织中广泛表达，并且构成治疗纤维化性肺疾病的有吸引力的靶标。本文中，我们介绍了基于新型喹啉的hFP-R拮抗剂的研究，包括合成和详细的结构-活性关系（SAR）。从我们公司的化合物文库的高通量筛选（HTS）命中开始，多参数的改进，包括相对口服生物利用度增加˚F_相对从3％到≥100％-导致了一种高效且选择性的hFP-R拮抗剂，并从悬浮液中完全吸收。据我们所知，BAY-6672（46）代表了第一个报道的FP-R拮抗剂，该拮抗剂在临床前动物肺纤维化动物模型中具有体内疗效，从而为IPF中的新治疗选择铺平了道路。