Biological characterization of new inhibitors of microsomal PGE synthase-1 in preclinical models of inflammation and vascular tone.
Br J Pharmacol
; 176(24): 4625-4638, 2019 12.
Article
em En
| MEDLINE
| ID: mdl-31404942
ABSTRACT
BACKGROUND AND PURPOSE:
Microsomal PGE synthase-1 (mPGES-1), the inducible synthase that catalyses the terminal step in PGE2 biosynthesis, is of high interest as therapeutic target to treat inflammation. Inhibition of mPGES-1 is suggested to be safer than traditional NSAIDs, and recent data demonstrate anti-constrictive effects on vascular tone, indicating new therapeutic opportunities. However, there is a lack of potent mPGES-1 inhibitors lacking interspecies differences for conducting in vivo studies in relevant preclinical disease models. EXPERIMENTALAPPROACH:
Potency was determined based on the reduction of PGE2 formation in recombinant enzyme assays, cellular assay, human whole blood assay, and air pouch mouse model. Anti-inflammatory properties were assessed by acute paw swelling in a paw oedema rat model. Effect on vascular tone was determined with human ex vivo wire myography. KEYRESULTS:
We report five new mPGES-1 inhibitors (named 934, 117, 118, 322, and 323) that selectively inhibit recombinant human and rat mPGES-1 with IC50 values of 10-29 and 67-250 nM respectively. The compounds inhibited PGE2 production in a cellular assay (IC50 values 0.15-0.82 µM) and in a human whole blood assay (IC50 values 3.3-8.7 µM). Moreover, the compounds blocked PGE2 formation in an air pouch mouse model and reduced acute paw swelling in a paw oedema rat model. Human ex vivo wire myography analysis showed reduced adrenergic vasoconstriction after incubation with the compounds. CONCLUSION AND IMPLICATIONS These mPGES-1 inhibitors can be used as refined tools in further investigations of the role of mPGES-1 in inflammation and microvascular disease.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Artérias
/
Dinoprostona
/
Edema
/
Inibidores Enzimáticos
/
Prostaglandina-E Sintases
/
Anti-Inflamatórios
/
Tono Muscular
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article