RESUMO
High-throughput screening for the induction of a luciferase reporter gene in a thrombopoietin (TPO)-responsive cell line resulted in the identification of 4-diazo-3-hydroxy-1-naphthalenesulfonic acids as TPO mimics. Modification of the core structure and adjustment of unwanted functionality resulted in the development of (5-oxo-1,5-dihydropyrazol-4-ylidene)hydrazines which exhibited efficacies equivalent to those of TPO in several cell-based assays designed to measure thrombopoietic activity. Furthermore, these compounds elicited biochemical responses in TPO-receptor-expressing cells similar to those in TPO itself, including kinase activation and protein phosphorylation. Potencies for the best compounds were high for such low molecular weight compounds (MW < 500) with EC(50) values in the region of 1-20 nM.
Assuntos
Compostos Azo/síntese química , Hidrazinas/síntese química , Megacariócitos/efeitos dos fármacos , Naftalenossulfonatos/síntese química , Proteínas de Neoplasias , Pirazóis/síntese química , Receptores de Citocinas , Trombopoetina/química , Animais , Compostos Azo/química , Compostos Azo/farmacologia , Divisão Celular , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Ensaio de Desvio de Mobilidade Eletroforética , Ativação Enzimática , Genes Reporter , Hidrazinas/química , Hidrazinas/farmacologia , Luciferases/genética , Luciferases/metabolismo , Camundongos , Mimetismo Molecular , Peso Molecular , Naftalenossulfonatos/química , Naftalenossulfonatos/farmacologia , Fosforilação , Fosfotransferases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Receptores de Trombopoetina , Relação Estrutura-Atividade , Trombopoetina/metabolismoRESUMO
A peptide RGD analog containing a novel 2-aminopyridine arginine mimetic was discovered to have good affinity and selectivity for the vitronectin receptor. Incorporation of the 2-aminopyridine arginine mimetic into the 3-oxo-1,4-benzodiazepine-2-acetic acid integrin antagonist series led to novel and potent nonpeptide vitronectin receptor antagonists with promising levels of oral bioavailability.