RESUMO
A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRß selectivity. The LXRß selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2µM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/sangue , Imidazóis/farmacologia , Fígado/efeitos dos fármacos , Receptores Nucleares Órfãos/agonistas , Pirazóis/farmacologia , Sulfonas/farmacologia , Animais , Agonismo Parcial de Drogas , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Fígado/metabolismo , Receptores X do Fígado , Camundongos , Modelos Moleculares , Estrutura Molecular , Plasma/química , Pirazóis/química , Pirazóis/farmacocinética , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacocinética , Distribuição Tecidual , Triglicerídeos/metabolismoRESUMO
Mass spectrometry (MS)-based enzyme assay has been shown to be a useful tool for screening enzymatic activities from environmental samples. Recently, reported approaches for high-specificity multiplexed characterization of enzymatic activities allow for providing detailed information on the range of enzymatic products and monitoring multiple enzymatic reactions. However, the throughput has been limited by the slow liquid-liquid handling and manual analysis. This rapid communication demonstrates the integration of acoustic sample deposition with nanostructure initiator mass spectrometry (NIMS) imaging to provide reproducible measurements of multiple enzymatic reactions at a throughput that is tenfold to 100-fold faster than conventional MS-based enzyme assay. It also provides a simple means for the visualization of multiple reactions and reaction pathways.
Assuntos
Ensaios Enzimáticos/instrumentação , Ensaios de Triagem em Larga Escala/instrumentação , Nanoestruturas/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/instrumentação , Acústica , Aspergillus niger/enzimologia , Bacillus/enzimologia , Ensaios Enzimáticos/economia , Desenho de Equipamento , Glicosídeo Hidrolases/metabolismo , Ensaios de Triagem em Larga Escala/economia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/economia , Fatores de Tempo , Xilosidases/metabolismoRESUMO
The design and synthesis of a series of highly functionalized pyrano-[2,3b]-pyridines is described. These compounds were assayed for their ability to block the I(Kur) channel encoded by the gene hKV1.5 in patch-clamped L-929 cells. Six of the compounds in this series showed sub-micromolar activity, the most potent being 4-(4-ethyl-benzenesulfonylamino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3b]-pyridine-6-carboxylic acid ethyl-phenyl-amide with an IC(50) of 378 nM.
Assuntos
Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Piranos/química , Piridinas/síntese química , Piridinas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Estrutura Molecular , Bloqueadores dos Canais de Potássio/química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRß activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15. The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile.
RESUMO
K(V)1.5 blockers have the potential to be atrium-selective agents for treatment of atrial fibrillation. The benzopyrans provide a template for the synthesis of potent and selective K(V)1.5 blockers.