Potent analogues of etiprednol dicloacetate, a second generation of soft corticosteroids.
J Pharm Pharmacol
; 69(12): 1745-1753, 2017 Dec.
Article
em En
| MEDLINE
| ID: mdl-28980320
ABSTRACT
OBJECTIVES:
Loteprednol etabonate (LE) is the first, highly successful soft corticosteroid (SC) designed using the 'inactive metabolite' approach, starting with ∆1 -cortienic acid (d-CA). The next generation of SCs based on d-CA was etiprednol dicloacetate (ED). The 17α-dichloroacetyl function serves both as a unique pharmacophore and as the source of the molecule's softness. Highly potent SCs were designed based on a combination of ED and LE, introducing 6, 9 and 16 substituents in the molecule.METHODS:
The new 6α, 9α, 16α and ß 17α-dichloroacetyl 17ß-esters were synthesized from the correspondingly substituted ∆1 -cortienic acids. The anti-inflammatory activity was assessed using LPS-induced TNF α-release under various conditions to determine intrinsic activity vs. systemic biological stability. In vivo anti-inflammatory activity was studied in the widely used ovalbumin-sensitized and ovalbumin-challenged Brown Norway rat model. KEYFINDINGS:
The 6α or 9α-fluoro substitution produced highly potent corticosteroids, but the 17α-dichloroacetyl substituent provided 'softness' in all cases. Local application of these steroids will significantly reduce systemic activity, due to the facile hydrolytic deactivation of these molecules.CONCLUSIONS:
A 17α-dichloroacetyl derivative of fluticasone (FLU) is highly potent but much safer than the currently used propionate or furoate ester.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Necrose Tumoral alfa
/
Corticosteroides
/
Etabonato de Loteprednol
/
Anti-Inflamatórios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Pharm Pharmacol
Ano de publicação:
2017
Tipo de documento:
Article