新型溶血磷脂酸1型受体环己基氨基酸拮抗剂治疗肺纤维化。

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-01-23 eCollection Date: 2025-02-13 DOI:10.1021/acsmedchemlett.4c00559

Marta Giuliani, Andrea Rizzi, Mafalda Pagano, Luca F Raveglia, Francesca Saccani, Maria Rosaria Di Lascia, Margherita Interlandi, Tonia Simona Nardella, Gessica Marchini, Annalisa Murgo, Laura Tigli, Alice Pappani, Anna Maria Capelli, Sergio Xanxo Fernandez, Paola Puccini, Gino Villetti, Maurizio Civelli, Claudia Beato, Elisa Moro, Claudia Mundi, Rosaria Remelli, Elisabetta Armani

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引用次数: 0

摘要

溶血磷脂酸（LPA）是一种通过与G蛋白偶联受体（LPA1-6）结合而激活不同生物学功能的磷脂。其中，LPA1受体在调节纤维化过程中的作用是众所周知的，使其成为肺纤维化和其他纤维化疾病的治疗靶点。在此，我们报道了一种新的LPA1拮抗剂的研究，用于口服治疗特发性肺纤维化，重点是肝胆安全。化合物7在体外和体内均表现出优异的疗效，在PD研究和啮齿动物肺纤维化模型中均显示出显著的疗效，具有良好的体外肝脏安全性。然而，在剂量范围发现（DRF）毒性研究中，化合物7在潜在的肝胆毒性方面不能确保安全性，导致其开发停止。

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Novel Cyclohexyl Amido Acid Antagonists of Lysophosphatidic Acid Type 1 Receptor for the Treatment of Pulmonary Fibrosis.

Lysophosphatidic acid (LPA) is a phospholipid activating different biological functions by binding to G protein-coupled receptors (LPA_1-6). Among these, the role of the LPA₁ receptor in modulating fibrotic processes is well-known, making it a therapeutic target for pulmonary fibrosis and other fibrotic disorders. Herein we report the search for a new class of LPA₁ antagonists for the oral treatment of idiopathic pulmonary fibrosis with a focus on hepatobiliary safety. Compound 7 excelled in in vitro and in vivo efficacy, showing significant efficacy both in PD studies and in a rodent lung fibrosis model, with a promising in vitro hepatic safety profile. However, in a dose range finding (DRF) toxicity study, compound 7 did not ensure safety regarding potential hepatobiliary toxicity, leading to its development being halted.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.