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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry


ISSN (Print): 1871-5230
ISSN (Online): 1875-614X

Research Article

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

Author(s): Lenisa Dandara dos Santos, Thamires Quadros Froes, Miriam Cristina Contin de Melo, Gloria Emília Petto de Souza, Denis de Melo Soares and Marcelo Santos Castilho*

Volume 20 , Issue 3 , 2021

Published on: 08 December, 2020

Page: [271 - 281] Pages: 11

DOI: 10.2174/1871523019999201208202831

Price: $65


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.

Keywords: mPGES-1, expression inhibitor, antipyretic, fever, PGE2, COX-2 inhibition.

Graphical Abstract
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