RESUMO
A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.
Assuntos
Pirimidinas/química , Receptores de Glutamato Metabotrópico/química , Estirenos/química , Administração Oral , Regulação Alostérica , Animais , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Ensaios de Triagem em Larga Escala , Humanos , Modelos Animais , Atividade Motora/fisiologia , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/uso terapêuticoRESUMO
We have been exploring the potential of 5-HT(2B) antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonism of the 5-HT(2B) receptor, (b) low impact of serum proteins on potency, and (c) desirable pharmacokinetic properties. This Letter describes our investigation of a biphenyl benzimidazole class of compounds that resulted in 5-HT(2B) antagonists possessing the above attributes. Improving potency in a human serum albumin shift assay proved to be the most significant SAR discovery.
Assuntos
Receptor 5-HT2B de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacocinética , Animais , Sítios de Ligação , Masculino , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptor 5-HT2B de Serotonina/química , Antagonistas da Serotonina/classificaçãoRESUMO
High-throughput screening against the human sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.
Assuntos
Carbazóis/síntese química , Inibidores de Histona Desacetilases , Indóis/síntese química , Sirtuínas/antagonistas & inibidores , Animais , Disponibilidade Biológica , Células CHO , Carbazóis/química , Carbazóis/farmacologia , Permeabilidade da Membrana Celular , Cricetinae , Cricetulus , Estabilidade de Medicamentos , Fluorometria , Histona Desacetilases/química , Humanos , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , NAD/química , NAD+ Nucleosidase/química , Niacinamida/química , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Sirtuína 1 , Sirtuínas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.