LPA and Autotaxin: Potential Drug Targets in Asthma?

Georas, Steve N.

doi:10.1007/s12013-021-01023-7

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…Among these sub-ATX and Lp-PLA2 hold importance in asthma. In vitro studies have demonstrated that ATX activates various cell types implicated in airway inflammation [23]; meanwhile, Lp-PLA2 is an enzyme associated with inflammation and has been implicated in the pathogenesis of various diseases, including asthma [9]. However, our study did not find these proinflammatory substances to have prognostic value.…”

Section: Discussioncontrasting

confidence: 77%

Novel Serum Biomarkers for Patients with Allergic Asthma Phenotype

Palacionyte,

Januskevicius,

Vasyle

et al. 2024

Biomedicines

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In distinguishing the allergic asthma (AA) phenotype, it has been identified that specific biomarkers could assist; however, none of them are considered ideal. This study aimed to analyze three groups of biologically active substances in the serum. Twenty steroid-free AA patients, sensitized to Dermatophagoides pteronyssinus, and sixteen healthy subjects (HSs) were enrolled in this study. Blood samples were collected from all patients. Additionally, all AA patients underwent a bronchial allergen challenge (BAC) with Dermatophagoides pteronyssinus, all of which were positive, and blood samples were collected again 24 h later. The concentrations of ten biologically active substances were measured in the serum samples, using enzyme-linked immunosorbent assay (ELISA) and the Luminex® 100/200™ System technology for bead-based multiplex and singleplex immunoassays. Descriptive and analytical statistical methods were used. A p-value of 0.05 or lower was considered statistically significant. The soluble interleukin 5 receptor subunit alpha (sIL-5Rα) and thioredoxin 1 (TRX1) concentrations were significantly increased, whereas those of tyrosine-protein kinase Met (MET), pentraxin 3 (PTX3), and I C-telopeptide of type I collagen (ICTP) were decreased in the AA group compared with the HS group. A significant positive correlation was noted for sIL-5Rα with fractional exhaled nitric oxide (FeNO), blood eosinophil (EOS) count, and total immunoglobulin E (IgE) levels, and a negative correlation was noted with forced expiratory volume in 1 s (FEV1). Moreover, PTX3 showed negative correlations with blood EOS count and total IgE levels, whereas ICTP exhibited a negative correlation with the blood EOS count. In conclusion, this study demonstrated that the serum concentrations of MET, PTX3, TRX1, ICTP, and particularly sIL-5Rα could potentially serve as biomarkers of the AA phenotype.

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Section: Discussioncontrasting

confidence: 77%

Novel Serum Biomarkers for Patients with Allergic Asthma Phenotype

Palacionyte,

Januskevicius,

Vasyle

et al. 2024

Biomedicines

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“…Studies in human patients as well as animal disease models revealed links between the ATX-LPA-LPAR1 signaling axis and fibrotic diseases in the lungs, kidneys, and skin, , inflammatory diseases including asthma, ,− cardiovascular diseases, and cancer. ,,, …”

Section: Introductionmentioning

confidence: 99%

Discovery of the Novel, Orally Active, and Selective LPA1 Receptor Antagonist ACT-1016-0707 as a Preclinical Candidate for the Treatment of Fibrotic Diseases

Lescop,

Birker,

Brotschi

et al. 2024

J. Med. Chem.

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Piperidine 3 is a potent and selective lysophosphatidic acid receptor subtype 1 receptor (LPAR1) antagonist that has shown efficacy in a skin vascular leakage target engagement model in mice. However, compound 3 has very high human plasma protein binding and high clearance in rats, which could significantly hamper its clinical development. Continued lead optimization led to the potent, less protein bound, metabolically stable, and orally active azetidine 17. Rat pharmacokinetics (PK) studies revealed that 17 accumulated in the liver. In vitro studies indicated that 17 is an organic anion co-transporting polypeptide 1B1 (OATP1B1) substrate. Although analogue 24 was no longer a substrate of OATP1B1, PK studies suggested that the compound undergoes enterohepatic recirculation. Replacing the carboxylic acidic side chain by a non-acidic sulfamide moiety and further fine-tuning of the scaffold yielded the potent, orally active LPAR1 antagonist 49, which was selected for preclinical development for the treatment of fibrotic diseases.

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“…ATX , and LPAR1 , are ubiquitously expressed, and based on LPA’s implication in many pivotal cellular processes, the ATX-LPA receptor axis was proposed as a viable target to treat cardiovascular, inflammatory, ,− and proliferative diseases. ,− Remarkably, LPAR1-deficient mice showed attenuated vascular leakage and fibrosis in a bleomycin-induced lung fibrosis model . Furthermore, elevated levels of LPA were found in bronchoalveolar lavage fluid (BALF) and exhaled breath condensate from patients with idiopathic pulmonary fibrosis (IPF), , suggesting continuous activation of LPAR1 by its ligand LPA as a key mechanism contributing to fibrosis progression.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Orally Active, Selective LPA Receptor Type 1 Antagonist, 4-(4-(2-Isopropylphenyl)-4-((2-methoxy-4-methylphenyl)carbamoyl)piperidin-1-yl)-4-oxobutanoic Acid, with a Distinct Molecular Scaffold

Lescop,

Brotschi,

Williams

et al. 2024

J. Med. Chem.

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Lysophosphatidic acid receptor 1 (LPAR1) antagonists show promise as potentially novel antifibrotic treatments. In a human LPAR1 β-arrestin recruitment-based high-throughput screening campaign, we identified urea 19 as a hit with a LPAR1 IC 50 value of 5.0 μM. Hit-to-lead activities revealed that one of the urea nitrogen atoms can be replaced by carbon and establish the corresponding phenylacetic amide as a lead structure for further optimization. Medicinal chemistry efforts led to the discovery of piperidine 18 as a potent and selective LPAR1 antagonist with oral activity in a mouse model of LPA-induced skin vascular leakage. The molecular scaffold of 18 shares no obvious structural similarity with any other LPAR1 antagonist disclosed so far.

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LPA and Autotaxin: Potential Drug Targets in Asthma?

Cited by 5 publications

References 26 publications

Novel Serum Biomarkers for Patients with Allergic Asthma Phenotype

Novel Serum Biomarkers for Patients with Allergic Asthma Phenotype

Discovery of the Novel, Orally Active, and Selective LPA1 Receptor Antagonist ACT-1016-0707 as a Preclinical Candidate for the Treatment of Fibrotic Diseases

Discovery of a Novel Orally Active, Selective LPA Receptor Type 1 Antagonist, 4-(4-(2-Isopropylphenyl)-4-((2-methoxy-4-methylphenyl)carbamoyl)piperidin-1-yl)-4-oxobutanoic Acid, with a Distinct Molecular Scaffold

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