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A Potent and Selective Human Prostaglandin F (FP) Receptor Antagonist (BAY-6672) for the Treatment of Idiopathic Pulmonary Fibrosis (IPF).
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-24 , DOI: 10.1021/acs.jmedchem.0c00834 Hartmut Beck 1 , Tobias Thaler 1 , Daniel Meibom 1 , Mark Meininghaus 1 , Hannah Jörißen 1 , Lisa Dietz 1 , Carsten Terjung 1 , Michaela Bairlein 1 , Clemens-Jeremias von Bühler 1 , Sonja Anlauf 1 , Chantal Fürstner 1 , Timo Stellfeld 2 , Dirk Schneider 1 , Kersten M Gericke 1 , Thomas Buyck 1 , Kai Lovis 1 , Uwe Münster 1 , Johanna Anlahr 1 , Elisabeth Kersten 1 , Guillaume Levilain 1 , Virginia Marossek 1 , Raimund Kast 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-24 , DOI: 10.1021/acs.jmedchem.0c00834 Hartmut Beck 1 , Tobias Thaler 1 , Daniel Meibom 1 , Mark Meininghaus 1 , Hannah Jörißen 1 , Lisa Dietz 1 , Carsten Terjung 1 , Michaela Bairlein 1 , Clemens-Jeremias von Bühler 1 , Sonja Anlauf 1 , Chantal Fürstner 1 , Timo Stellfeld 2 , Dirk Schneider 1 , Kersten M Gericke 1 , Thomas Buyck 1 , Kai Lovis 1 , Uwe Münster 1 , Johanna Anlahr 1 , Elisabeth Kersten 1 , Guillaume Levilain 1 , Virginia Marossek 1 , Raimund Kast 1
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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.
中文翻译:
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。
更新日期:2020-10-22
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
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。