2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: attenuation of hERG binding and improved HDLc-raising efficacy.
Bioorg Med Chem Lett
; 21(9): 2597-600, 2011 May 01.
Article
em En
| MEDLINE
| ID: mdl-21398121
ABSTRACT
The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzoxazóis
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Transativadores
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Proteínas de Transferência de Ésteres de Colesterol
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HDL-Colesterol
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article