Structure-activity relationship study of β -oxidation resistant indole-based 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) receptor antagonists

Ye, Qiuji; Chourey, Shishir; Wang, Rui; Chintam, Nagendra Reddy; Gravel, Sylvie; Powell, William S.; Rokach, Joshua

doi:10.1016/j.bmcl.2017.08.034

Cited by 5 publications

(2 citation statements)

References 17 publications

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“…In fact, the metabolic stability in the hepatocyte of 7 was very low as shown in Table (remaining % in hepatocyte, human: 29%, rat: 10%). While several approaches have been reported to prevent β-oxidation, , we decided to introduce a dimethyl group adjacent to the carboxyl group in 7 considering its low measured LogD value (LogD 7.4 = 0.51). Introduction of dimethyl group at the α and β carbon positions of the carboxyl group in 7 afforded compounds 8 and 9 , respectively, which exhibited improved metabolic stability in hepatocytes with an improvement in the hATX inhibitory activity ( 8 , IC 50 = 0.024 μM; 9 , IC 50 = 0.017 μM).…”

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confidence: 99%

ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model

Iwaki

Ohhata

Nakatani

et al. 2020

ACS Med. Chem. Lett.

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Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (20), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (20), which enhanced the antitumor effect of paclitaxel in a breast cancer model.

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mentioning

confidence: 99%

ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model

Iwaki

Ohhata

Nakatani

et al. 2020

ACS Med. Chem. Lett.

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“…Interestingly, Powell and coworkers used a different approach on the basis of structure-activity relationships to synthesize several OXE receptor antagonists, including S-230, S-264, S-C025, and S-Y048 [90][91][92][93][94]. And the S-Y048 was the meta-chloro derivative of S-C025.…”

Section: Oxe Receptor Antagonistsmentioning

confidence: 99%

Biological Roles of 5-Oxo-6,8,11,14-Eicosatetraenoic Acid and the OXE Receptor in Allergic Diseases: Collegium Internationale Allergologicum Update 2024

Lin,

Dai,

Wei

et al. 2024

Int Arch Allergy Immunol

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Background: 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-Oxo-ETE) is a metabolite of arachidonic acid shown to promote biological activities in different cell types. Summary: 5-Oxo-ETE is synthesized from the 5-lipoxygenase product 5S-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) in the presence of the nicotinamide adenine dinucleotide phosphate (NADP)+-dependent enzyme 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Under some conditions that promote oxidation of NADPH to NADP+, such as the respiratory burst in phagocytic cells, eosinophils, and neutrophils, oxidative stress in monocytes and dendritic cells, and cell death, 5-Oxo-ETE synthesis can be dramatically increased. In addition, 5-Oxo-ETE can also be formed in the absence of 5-lipoxygenase in cells through transcellular biosynthesis by inflammatory cell-derived 5S-HETE. This compound performs its biological activities by the highly selective Gi/o-coupled OXE receptor, which is highly expressed on eosinophils, neutrophils, basophils, and monocytes. As such, 5-Oxo-ETE is a potent chemoattractant for these inflammatory cells, especially for eosinophils. Key Messages: Although the pathophysiological role of 5-Oxo-ETE is not clearly understood, 5-Oxo-ETE may be a significant mediator in allergic diseases, such as allergic asthma, allergic rhinitis, and atopic dermatitis. And targeting the OXE receptor may be a novel therapy for this kind of inflammatory condition. Nowadays, selective OXE receptor antagonists are currently under investigation and could become potential therapeutic agents in allergy.

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Targeting the OXE receptor as a potential novel therapy for asthma

Powell

Rokach

2020

Biochemical Pharmacology

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Structure-activity relationship study of β -oxidation resistant indole-based 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) receptor antagonists

Cited by 5 publications

References 17 publications

ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model

ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model

Biological Roles of 5-Oxo-6,8,11,14-Eicosatetraenoic Acid and the OXE Receptor in Allergic Diseases: Collegium Internationale Allergologicum Update 2024

Targeting the OXE receptor as a potential novel therapy for asthma

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