Discovery of Novel Autotaxin Inhibitors Bearing the 4,5,6,7-Tetrahydro-7H-Pyrazolo[3,4-c]Pyridine-7-One Core for Pulmonary Fibrosis Therapy

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Jiahe Zhang, Jiachen Zhang, Jiandong Li, Deyi Ma, Zehui Tan, Xin Zhai
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引用次数: 0

Abstract

Pulmonary fibrosis (PF) is a progressive and fatal disease, and recent studies have revealed its key role in the autotaxin (ATX)-lysophosphatidic acid (LPA) signaling pathway, revealing the therapeutic potential of targeting ATX. Herein, starting from PAT-409, a series of novel ATX inhibitors containing the 4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one core were designed to improve the pharmacological activity and physicochemical properties. The most promising compound 19 exhibited potent ATX inhibition (IC50 = 4.2 nM) and significantly reduced lipophilicity (cLogP = 2.992) compared with PAT-409 (IC50 = 4.9 nM, cLogP = 7.647). Molecular dynamics simulations indicated that 19 bound to the ATX protein in a highly stable manner. Furthermore, predictive analyses of drug-like properties and toxicity uncovered that 19 demonstrated comparable safety to PAT-409 while exhibiting significantly superior drug-like characteristics. This study provides a promising ATX inhibitor for PF therapy.

含有4,5,6,7-四氢- 7h -吡唑啉[3,4-c]吡啶-7- one核心的新型自taxin抑制剂的发现用于肺纤维化治疗
肺纤维化(Pulmonary fibrosis, PF)是一种进行性致死性疾病,近年来的研究揭示了其在autotaxin (ATX)-lysophosphatidic acid (LPA)信号通路中的关键作用,揭示了靶向ATX的治疗潜力。本文从PAT-409开始,设计了一系列含有4,5,6,7-四氢- 7h -pyrazolo[3,4-c]吡啶-7- 1核心的新型ATX抑制剂,以提高其药理活性和理化性质。与PAT-409 (IC50 = 4.9 nM, cLogP = 7.647)相比,最有希望的化合物19表现出有效的ATX抑制(IC50 = 4.2 nM)和显著降低的亲脂性(cLogP = 2.992)。分子动力学模拟表明,19以高度稳定的方式与ATX蛋白结合。此外,药物样特性和毒性的预测分析发现,19种药物的安全性与PAT-409相当,同时表现出明显优于PAT-409的药物样特性。本研究为PF治疗提供了一种有前景的ATX抑制剂。
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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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