Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model.
Bioorg Med Chem Lett
; 25(11): 2280-4, 2015 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-25933594
ABSTRACT
Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide 6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively). Compound 6 exhibited potent inhibition of neutrophil influx in a rat model of pulmonary inflammation, and is hypothesized to interact with a unique intracellular binding site on CXCR2. Compound 6 (SX-576) is undergoing further investigation as a potential therapy for pulmonary inflammation.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ácidos Borônicos
/
Niacinamida
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Receptores de Interleucina-8A
/
Receptores de Interleucina-8B
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article