Identification of a novel series of potent and selective CCR6 inhibitors as biological probes.
Bioorg Med Chem Lett
; 28(18): 3067-3072, 2018 10 01.
Article
en En
| MEDLINE
| ID: mdl-30098865
ABSTRACT
CCR6 has been implicated in both autoimmune diseases and non-autoimmune diseases. Thus, inhibition of CCR6-dependent cell migration is an attractive strategy for their treatment. An orally available small molecule inhibitor of CCR6 could therefore be a useful biological probe for the pathophysiological studies. Initial SAR study of a hit compound provided potent N-benzenesulfonylpiperidine derivatives that suppressed CCL20-induced Gi signals. By subsequent scaffold morphing of the central ring and further optimization, we identified a novel series of 1,4-trans-1-benzenesulfonyl-4-aminocyclohexanes as potent and selective CCR6 inhibitors with good pharmacokinetic properties. Our compounds showed good correlation between Gi signal inhibitory activity and cell migration inhibitory activity in human CCR6-transfected CHO cells. In addition, representative compound 35 potently inhibited CCR6-dependent cell migration and the increase in ERK phosphorylation in human primary cells. Therefore, the compound could be used effectively as a biological probe against human CCR6.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Piperidinas
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Ciclohexanos
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Receptores CCR6
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Bibliotecas de Moléculas Pequeñas
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Aminas
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
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Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article