Pharmacological characterisation of CR6086, a potent prostaglandin E2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug

Arthritis Research & Therapy
Gianfranco CaselliLucio Claudio Rovati

Abstract

Prostaglandin E2 (PGE2) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD). CR6086 affinity and pharmacodynamics were studied in EP4-expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively. In immune cells, IL-6 and vascular endothelial growth factor (VEGF) expression were analysed by RT-PCR, and IL-23 and IL-17 release were measured by enzyme-linked immunosorbent assay (ELISA). In collagen-induced arthritis (CIA) models, rats or mice were immunised with bovine collagen type II. Drugs were administered orally (etanercept and methotrexate intraperitoneally) starting at disease onset. Arthritis progression was evaluated by oedema, clinical score and histopathology. Anti-collagen II immunoglobulin G antibodies were measured by ELISA. CR6086 showed selectivity and high affinity for the human E...Continue Reading

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Citations

Jan 11, 2019·Laboratory Investigation; a Journal of Technical Methods and Pathology·Kewei LiuChangwei Li
Feb 1, 2019·International Journal of Molecular Sciences·Abdul QadirAirong Qian
Oct 8, 2020·Scandinavian Journal of Immunology·Qi ChengYan Du
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Jul 27, 2021·Frontiers in Immunology·Jie HuangChao Liang
Aug 8, 2021·Cancers·Mousumi MajumderMuriel Brackstone

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Datasets Mentioned

BETA
MC216813

Methods Mentioned

BETA
scraping
saturation binding
AlphaScreen
enzyme-linked immunosorbent assay
ELISA
equilibrium dialysis
fluorescence-activated cell sorting
PMA

Clinical Trials Mentioned

NCT03163966

Software Mentioned

Prism
GraphPad

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