RESUMO
A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Convulsões/induzido quimicamente , Tiazóis/síntese química , Administração Oral , Animais , Expressão Gênica/efeitos dos fármacos , Infusões Intravenosas , Masculino , Miocárdio/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/efeitos adversos , Tiazóis/químicaRESUMO
A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.
Assuntos
Sistemas de Liberação de Medicamentos , Glucuronídeos/metabolismo , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/farmacologia , Fígado/efeitos dos fármacos , Mifepristona/administração & dosagem , Mifepristona/farmacologia , Receptores de Glucocorticoides/antagonistas & inibidores , Administração Oral , Fosfatase Alcalina/antagonistas & inibidores , Animais , Ligação Competitiva/efeitos dos fármacos , Dexametasona/farmacocinética , Circulação Êntero-Hepática , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glucocorticoides/farmacocinética , Glucuronídeos/farmacocinética , Antagonistas de Hormônios/farmacocinética , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Injeções Intravenosas , Microssomos Hepáticos/metabolismo , Mifepristona/farmacocinética , Compostos de Amônio Quaternário , Ratos , Ratos Sprague-Dawley , Tirosina Transaminase/antagonistas & inibidoresRESUMO
The synthesis, activity, metabolic stability, and pharmacokinetics of steroidal and nonsteroidal glucocorticoid receptor modulator-statin hybrids is reported. Potent steroidal antagonist-statin hybrids like 22 (h-GR binding IC(50)=7 nM) and nonsteroidal modulator hybrids like 16 (h-GR binding IC(50)=2 nM) were discovered. Appending a 'statin'-like diol-acid group to the modulators dramatically improved metabolic stability (and in some cases hepatocyte activity), but did not impart hepatoselectivity.