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羧酸生物电子等排体提高Nurr1激动剂的选择性。

Carboxylic Acid Bioisosteres Boost Nurr1 Agonist Selectivity.

作者信息

Stiller Tanja, Gege Christian, Saeb Wael, Vietor Jan, López-García Úrsula, Busch Romy, Kohlhof Hella, Vitt Daniel, Merk Daniel

机构信息

Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.

Immunic AG, 82166 Gräfelfing, Germany.

出版信息

J Med Chem. 2025 Jul 17. doi: 10.1021/acs.jmedchem.5c01140.

DOI:10.1021/acs.jmedchem.5c01140
PMID:40674328
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7617969/
Abstract

Nuclear receptor related 1 (Nurr1) is a neuronal ligand-activated transcription factor implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and multiple sclerosis, which has fueled the development of Nurr1 modulators. Among them, the clinically studied dihydroorotate dehydrogenase (DHODH) inhibitor vidofludimus was found to exhibit strong Nurr1 agonism. Here, we aimed to establish a vidofludimus-derived Nurr1 agonist lacking DHODH inhibitor potency as a tool. We explored bioisosteric replacement of the drug's carboxylate motif and succeeded in boosting selectivity for Nurr1 over DHODH to >100-fold. Dopaminergic neural cells treated with the optimized tetrazole-based Nurr1 agonist revealed induction of genes involved in neuroprotection and neuronal health, supporting the potential of Nurr1 activation in neurodegenerative diseases.

摘要

核受体相关蛋白1（Nurr1）是一种神经元配体激活转录因子，与包括阿尔茨海默病、帕金森病和多发性硬化症在内的神经退行性疾病有关，这推动了Nurr1调节剂的开发。其中，临床研究的二氢乳清酸脱氢酶（DHODH）抑制剂维托鲁单抗被发现具有强大的Nurr1激动作用。在此，我们旨在开发一种缺乏DHODH抑制活性的维托鲁单抗衍生的Nurr1激动剂作为工具。我们探索了该药物羧酸盐基序的生物电子等排体替代，并成功将对Nurr1的选择性提高到对DHODH的选择性的100倍以上。用优化后的基于四氮唑的Nurr1激动剂处理多巴胺能神经细胞，发现与神经保护和神经元健康相关的基因被诱导，这支持了在神经退行性疾病中激活Nurr1的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cec7/7617969/43d2700d275c/EMS207341-f015.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cec7/7617969/0cb1397e3007/EMS207341-f009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cec7/7617969/161137a85982/EMS207341-f010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cec7/7617969/addd55ee0c32/EMS207341-f011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cec7/7617969/9651e09dd529/EMS207341-f012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cec7/7617969/c04268278afa/EMS207341-f013.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cec7/7617969/43d2700d275c/EMS207341-f015.jpg

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Carboxylic Acid Bioisosteres Boost Nurr1 Agonist Selectivity.

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[2]
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[3]
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[6]
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[8]
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本文引用的文献

[1]
Structural and mechanistic profiling of Nurr1 modulation by vidofludimus enables structure-guided ligand design.

Commun Chem. 2025-5-21

[2]
A Nurr1 Agonist Derived from the Natural Ligand DHI Induces Neuroprotective Gene Expression.

J Med Chem. 2025-2-27

[3]
Tetrazoles: A multi-potent motif in drug design.

Eur J Med Chem. 2024-12-5

[4]
Development of Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing.

Commun Chem. 2024-6-29

[5]
Synthesis and Characterization of DHODH Inhibitors Based on the Vidofludimus Scaffold with Pronounced Anti-SARS-CoV-2 Activity.

ChemMedChem. 2024-10-1

[6]
Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial.

Neurol Neuroimmunol Neuroinflamm. 2024-5

[7]
Bioisoteres for carboxylic acids: From ionized isosteres to novel unionized replacements.

Bioorg Med Chem. 2024-4-15

[8]
Exploring Fatty Acid Mimetics as NR4A Ligands.

J Med Chem. 2023-11-23

[9]
Structure-Guided Design of Nurr1 Agonists Derived from the Natural Ligand Dihydroxyindole.

J Med Chem. 2023-10-12

[10]
Rejection of inappropriate synaptic partners in mouse retina mediated by transcellular FLRT2-UNC5 signaling.

Dev Cell. 2023-10-23

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