RESUMO
The discovery and SAR of a novel series of substituted 2,2-bisaryl-bicycloheptane inhibitors of 5-lipoxygenase activating protein (FLAP) are herein described. SAR studies have shown that 2,5-substitution on the exo-aryl group is optimal for potency. The most potent compounds in this series have an ortho-nitrogen aryl linked with a methyleneoxy as the 5-substituent and a polar group such as a urethane as the 2-substituent. One of the most potent compounds identified is the 5-benzothiazolymethoxy-2-pyridinylcarbamate derivative 2 (FLAP IC(50)=2.8 nM) which blocks 89% of ragweed induced urinary LTE(4) production in dogs (at an I.V. dose of 2.5 microg/kg/min). This compound inhibits calcium ionophore stimulated LTB(4) production in both human polymorphonuclear (PMN) leukocytes and human whole blood (IC(50)=2.0 and 33 nM, respectively).
Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Heptanos/farmacologia , Inibidores de Lipoxigenase/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas Ativadoras de 5-Lipoxigenase , Ambrosia/química , Animais , Compostos Bicíclicos com Pontes/síntese química , Proteínas de Transporte/metabolismo , Cães , Heptanos/síntese química , Humanos , Indóis/metabolismo , Indóis/farmacologia , Radioisótopos do Iodo/metabolismo , Leucotrieno D4/urina , Proteínas de Membrana/metabolismo , Estrutura Molecular , Neutrófilos/efeitos dos fármacos , Quinolinas/metabolismo , Quinolinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.
Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Inibidores da Fosfodiesterase 4 , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Disponibilidade Biológica , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacocinética , Desenho de Fármacos , Cobaias , Humanos , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacocinética , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacocinética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
L-454,560 is a potent phosphodiesterase 4 (PDE4) inhibitor which was identified as a development candidate for the treatment of asthma and chronic obstructive pulmonary disease (COPD). As part of the discovery of this compound, interspecies in vitro metabolism data was generated using liver microsomes and hepatocytes in order to understand the metabolic fate of the compound. In microsomes, metabolism of the 3-methyl-1,2,4-oxadiazole ring was the predominant pathway observed, including ring cleavage. In rat hepatocytes, hydroxylation of the methyl group on the oxadiazole ring and double-bond isomerization were the most abundant metabolites observed. No major species differences were found in terms of microsomal metabolite profiles. The use of LC with UV and MS detection is highlighted, as well as information from tandem mass spectrometry and NMR.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Hepatócitos/metabolismo , Microssomos Hepáticos/metabolismo , Quinolinas/farmacocinética , Animais , Cromatografia Líquida/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Cães , Humanos , Macaca mulatta , Espectrometria de Massas/métodos , Camundongos , Ratos , Saimiri , Especificidade da Espécie , Espectrofotometria Ultravioleta/métodosRESUMO
Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.
Assuntos
Nitrogênio/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Disponibilidade Biológica , Meia-Vida , Inibidores de Fosfodiesterase/farmacocinética , Quinolinas/farmacocinética , Ratos , SaimiriRESUMO
The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.
