Evidence map›Paper›PMID 40902199›Full record

ArticleChemMedChem2025

Development of Keap1-Nrf2 Protein-Protein Interaction Inhibitor Activating Intracellular Nrf2 Based on the Naphthalene-2-acetamide Scaffold, and its Anti-Inflammatory Effects.

Daisuke Yasuda, Kai Toyoshima, Koujin Kojima, Hanako Ishida, Kazuma Kaitoh, Riyo Imamura, Kayoko Kanamitsu, Hirotatsu Kojima, Megumi Funakoshi-Tago, Masanori Osawa and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in ChemMedChem, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Daisuke YasudaFaculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.ORCID https://orcid.org/0000-0002-3279-6854
Kai ToyoshimaDivision of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.
Koujin KojimaDivision of Physics for Life Functions, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.
Hanako IshidaDivision of Physics for Life Functions, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.
Kazuma KaitohCatalytic Chemistry Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8656, Japan.
Riyo ImamuraDrug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Kayoko KanamitsuDrug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Hirotatsu KojimaDrug Discovery Initiative, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Megumi Funakoshi-TagoDivision of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.
Masanori OsawaDivision of Physics for Life Functions, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.
Tomoyuki OheEducation Research Center for Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.
Tomoya HiranoFaculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.

Funding

Grants-in-Aid 22K07131Grants-in-Aid 23K06039Grants-in-Aid 24K02169Japan Science Society 2023-3028Life Science and Drug Discovery JP24ama121051Life Science and Drug Discovery JP24ama121053Life Science and Drug Discovery JP25ama121001
6 · The paper itself

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) axis is an attractive therapeutic target for various intractable diseases. Although protein-protein interaction inhibitors against Keap1-Nrf2 have been developed over the past decade, more structural expansion is needed to improve efficacy. In this article, several candidate compounds are designed and synthesized as novel Nrf2 activators and their intracellular Nrf2-activating effects are evaluated. Among the synthesized compounds, a novel naphthalene-1,4-(4-ethoxybenzensulfonamide) bearing a tertiary acetamide side chain at the 2-position strongly activated intracellular Nrf2. Particularly, the pyrrolidine-type acetamide compound showed the strongest intracellular Nrf2 activation. X-ray cocrystallography revealed that this compound can bind to the DC domain of Keap1. Additionally, the pyrrolidine-type acetamide compound induced the mRNA expression of the representative Nrf2 target genes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase 1. Moreover, the compound exhibited anti-inflammatory effects in a lipopolysaccharide-stimulated macrophage cell line. Conclusively, these results suggest that the pyrrolidine-type naphthalene-2-acetamide is a promising compound for the development of Nrf2 activators that can be applied to treat inflammatory diseases.

Indexed as

AcetamidesAnti-Inflammatory AgentsAnti-Inflammatory Agents, Non-SteroidalKelch-Like ECH-Associated Protein 1NaphthalenesNF-E2-Related Factor 2AnimalsDose-Response Relationship, DrugHumansLipopolysaccharidesMiceMolecular StructureRAW 264.7 CellsStructure-Activity RelationshipAcetamidesAnti-Inflammatory AgentsAnti-Inflammatory Agents, Non-SteroidalKEAP1 protein, humanKelch-Like ECH-Associated Protein 1LipopolysaccharidesnaphthaleneNaphthalenesNFE2L2 protein, humanNF-E2-Related Factor 2acetamidesanti‐inflammatory effectsKelch‐like ECH‐associated protein 1Nuclear factor erythroid 2‐related factor 2protein–protein interactions

Identifiers

PMID40902199
PMCPMC12597218

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.