RESUMO
Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use for HDAC inhibitors in oncology. Here we describe the first crystal structures of a human HDAC: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors. This work sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across the HDAC family. The structure also suggests how phosphorylation of Ser39 affects HDAC8 activity.
Assuntos
Histona Desacetilases/química , Proteínas Repressoras/química , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Histona Desacetilases/metabolismo , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Conformação Proteica , Proteínas Repressoras/metabolismo , Especificidade por SubstratoRESUMO
Efforts to improve the potency and pharmacokinetic properties of small molecule factor VIIa inhibitors are described. Small structural modifications to existing leads allow the modulation of half-life and clearance, potentially making these compounds suitable candidates for drug development.
Assuntos
Anticoagulantes/farmacocinética , Coagulação Sanguínea/efeitos dos fármacos , Fator VIIa/antagonistas & inibidores , Inibidores de Serina Proteinase/farmacocinética , Animais , Desenho de Fármacos , Meia-Vida , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The 4-amino-5-azaindole as an amidino-benzimidazole replacement is described. A series of potent and selective analogs were discovered and showed desirable ex vivo efficacy as measured by PT.
Assuntos
Fator VIIa/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Fator VIIa/metabolismo , Indóis/química , Estrutura Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Efforts toward developing orally bioavailable factor VIIa inhibitors starting from parenteral lead compound 1 are described. SAR resulted in improved physicochemical properties, leading to enhanced oral absorption in rat.
Assuntos
Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Fator VIIa/antagonistas & inibidores , Trombose/tratamento farmacológico , Administração Oral , Animais , Disponibilidade Biológica , Ratos , Relação Estrutura-Atividade , Trombina/antagonistas & inibidoresRESUMO
The discovery and development of 5-azaindole factor VIIa inhibitors will be described.
Assuntos
Compostos Aza/síntese química , Compostos Aza/farmacologia , Fator VIIa/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Compostos Aza/química , Cristalografia por Raios X , Fator VIIa/química , Fator VIIa/metabolismo , Indóis/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Highly selective and potent factor VIIa-tissue factor (fVIIa.TF) complex inhibitors were generated through structure-based design. The pharmacokinetic properties of an optimized analog (9) were characterized in several preclinical species, demonstrating pharmacokinetic characteristics suitable for once-a-day dosing in humans. Analog 9 inhibited platelet and fibrin deposition in a dose-dependent manner after intravenous administration in a baboon thrombosis model, and a pharmacodynamic concentration-response model was developed to describe the platelet deposition data. Results for heparin and enoxaparin (Lovenox) in the baboon model are also presented.