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

IF 3.5 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

Abstract

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.