Discovery and optimization of pyridyl-cycloalkyl-carboxylic acids as inhibitors of microsomal prostaglandin E synthase-1 for the treatment of endometriosis.
Bioorg Med Chem Lett
; 29(18): 2700-2705, 2019 09 15.
Article
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| MEDLINE
| ID: mdl-31362919
ABSTRACT
Here we report on novel and potent pyridyl-cycloalkyl-carboxylic acid inhibitors of microsomal prostaglandin E synthase-1 (PTGES). PTGES produces, as part of the prostaglandin pathway, prostaglandin E2 which is a well-known driver for pain and inflammation. This fact together with the observed upregulation of PTGES during inflammation suggests that blockade of the enzyme might provide a beneficial treatment option for inflammation related conditions such as endometriosis. Compound 5a, a close analogue of the screening hit, potently inhibited PTGES in vitro, displayed excellent PK properties in vitro and in vivo and demonstrated efficacy in a CFA-induced pain model in mice and in a rat dyspareunia endometriosis model and was therefore selected for further studies.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Ácidos Carboxílicos
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Endometriosis
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Inhibidores Enzimáticos
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Descubrimiento de Drogas
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Prostaglandina-E Sintasas
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2019
Tipo del documento:
Article