RESUMO
A series of phenyl sulfone substituted quinoxaline were prepared and the lead compound 13 (WYE-672) was shown to be a tissue selective LXR Agonist. Compound 13 demonstrated partial agonism for LXRbeta in kidney HEK-293 cells but did not activate Gal4 LXRbeta fusion proteins in huh-7 liver cells. Although 13 showed potent binding affinity to LXRbeta (IC(50) = 53 nM), it had little binding affinity for LXRalpha (IC(50) > 1.0 microM) and did not recruit any coactivator/corepressor peptides in the LXRalpha multiplex assay. However, compound 13 showed good agonism in THP-1 cells with respect to increasing ABCA1 gene expression and good potency on cholesterol efflux in THP-1 foam cells. In an eight-week lesion study in LDLR -/- mice, compound 13 showed reduction of aortic arch lesion progression and no plasma or hepatic triglyceride increase. These results suggest quinoxaline 13 may have an improved biological profile for potential use as a therapeutic agent.
Assuntos
Receptores Nucleares Órfãos/agonistas , Quinoxalinas/síntese química , Sulfonas/síntese química , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Animais , Área Sob a Curva , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Linhagem Celular , Colesterol/metabolismo , Duodeno/metabolismo , Meia-Vida , Humanos , Rim/metabolismo , Fígado/metabolismo , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Especificidade de Órgãos , Receptores Nucleares Órfãos/genética , Quinoxalinas/química , Quinoxalinas/farmacologia , Ensaio Radioligante , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Ativação Transcricional , Triglicerídeos/metabolismoRESUMO
A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule resulted in several structures with improved properties and culminated in the discovery of 6-([4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl] methyl)quinoxaline (WAY-207024). The compound was shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral administration.
Assuntos
Benzimidazóis/síntese química , Quinoxalinas/síntese química , Receptores LHRH/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Ligação Competitiva , Disponibilidade Biológica , Meia-Vida , Humanos , Técnicas In Vitro , Hormônio Luteinizante/sangue , Masculino , Microssomos Hepáticos/metabolismo , Orquiectomia , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Quinoxalinas/química , Quinoxalinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeRESUMO
We synthesized and evaluated a novel series of 2-carboxylic acid indole-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). Systematic modification of the N-1 position and the 5-position of the indole scaffold resulted in the identification of several compounds that showed good potency against PAI-1 in the spectrophotometric assay. This potency did not always translate to the antibody assay. Solubility and serum protein binding studies on selected analogs revealed that protein binding might be a factor in the poor correlation between the two assays.
