Structure-activity relationship study and discovery of indazole 3-carboxamides as calcium-release activated calcium channel blockers.
Bioorg Med Chem Lett
; 27(3): 393-397, 2017 02 01.
Article
em En
| MEDLINE
| ID: mdl-28057422
ABSTRACT
Aberrant activation of mast cells contributes to the development of numerous diseases including cancer, autoimmune disorders, as well as diabetes and its complications. The influx of extracellular calcium via the highly calcium selective calcium-release activated calcium (CRAC) channel controls mast cell functions. Intracellular calcium homeostasis in mast cells can be maintained via the modulation of the CRAC channel, representing a critical point for therapeutic interventions. We describe the structure-activity relationship study (SAR) of indazole-3-carboxamides as potent CRAC channel blockers and their ability to stabilize mast cells. Our SAR results show that the unique regiochemistry of the amide linker is critical for the inhibition of calcium influx, the release of the pro-inflammatory mediators ß-hexosaminidase and tumor necrosis factor α by activated mast cells. Thus, the indazole-3-carboxamide 12d actively inhibits calcium influx and stabilizes mast cells with sub-µM IC50. In contrast, its reverse amide isomer 9c is inactive in the calcium influx assay even at 100µM concentration. This requirement of the specific 3-carboxamide regiochemistry in indazoles is unprecedented in known CRAC channel blockers. The new structural scaffolds described in this report expand the structural diversity of the CRAC channel blockers and may lead to the discovery of novel immune modulators for the treatment of human diseases.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Bloqueadores dos Canais de Cálcio
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Canais de Cálcio
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Cálcio
/
Amidas
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article