Triazol-phenyl Antipyretic Derivatives Inhibit mPGES-1 mRNA Levels in LPS-Induced RAW 264.7 Macrophage Cells

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BACKGROUND: Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the terminal step of prostaglandin E2 (PGE2) production, which plays an important role in the regulation of febrile response. In our previous work, ligand-based pharmacophore models, built with mPGES-1 inhibitors, were employed to identify a novel series of compounds that reduce the febrile response in rats.

OBJECTIVES: The study aimed to evaluate the mechanism of action of the most active compound (1).

METHODS: For in vivo assays, rats were pretreated with the antipyretic compounds 1-8, 30 min before LPS injection. For in vitro assays, RAW 264.7 macrophage cells were incubated with the antipyretic compounds 1-8 for 1 hour before LPS stimulus. After 16 h, quantitative real-time PCR was carried out. Additionally, the PGE2 concentration in the hypothalamus was quantified by ELISA and the inhibitory effect of N-cyclopentyl-N'-[3-(3-cyclopropyl-1H-1,2,4-triazol- 5-yl)phenyl]ethanediamide (1) over human COX-2 enzymatic activity was determined with a COX Colorimetric Inhibitor Screening Assay Kit.

RESULTS: Compound 1 and CAY10526 showed comparable efficacy to reduce the febrile response when injected i.v. (compound 1: 63.10%, CAY10526: 70.20%). Moreover, compound 1 significantly reduced the mPGES-1 mRNA levels, in RAW264.7 cells, under inflammatory conditions. A chemically-similar compound (8-) also significantly reduced the mRNA levels of the gene target. On the other hand, compounds 6 and 7, which are also somewhat similar to compound 1, did not significantly impact mPGES-1 mRNA levels.

CONCLUSIONS: PGE2 concentration reduction in the hypothalamus, due to compound 1 central injection, is related to decreased mPGES-1 mRNA levels but not to COX-2 inhibition (IC50> 50 μM). Therefore, compound 1 is a promising lead for innovative antipyretic drug development.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:20

Enthalten in:

Anti-inflammatory & anti-allergy agents in medicinal chemistry - 20(2021), 3 vom: 08., Seite 271-281

Sprache:

Englisch

Beteiligte Personen:

Dos Santos, Lenisa Dandara [VerfasserIn]
Froes, Thamires Quadros [VerfasserIn]
Contin de Melo, Miriam Cristina [VerfasserIn]
Petto de Souza, Gloria Emília [VerfasserIn]
Soares, Denis de Melo [VerfasserIn]
Castilho, Marcelo Santos [VerfasserIn]

Links:

Volltext

Themen:

Antipyretic
Antipyretics
COX-2 inhibition.
Cyclooxygenase 2
EC 1.14.99.1
EC 5.3.99.3
Expression inhibitor
Fever
Journal Article
Lipopolysaccharides
MPGES-1
PGE2
Prostaglandin-E Synthases
Ptges protein, mouse
Ptges protein, rat
RNA, Messenger

Anmerkungen:

Date Completed 06.04.2022

Date Revised 31.05.2022

published: Print

Citation Status MEDLINE

doi:

10.2174/1871523019999201208202831

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM318577569