RESUMO
1H Time-Domain Nuclear Magnetic Resonance (TD-NMR) is used to characterize solutions of antibodies that simulate biologic pharmaceutical formulations. The results from these measurements are compared with those from solutions in which the concentration or identity of the antibody has been altered. TD-NMR is shown to be very sensitive to differences in the amount of antibody in solution, with the ability to detect variations in as low as 2 mg/mL. It is therefore capable, by comparison with data from known formulations, of determining whether a particular sample is likely to be of an authentic biologic formulation. This method expands on the previous use of HPLC, UV/VIS, Near-IR and High-Resolution NMR to detect adulterated pharmaceutical materials. While the sensitivity of the method is high, it is a fingerprinting methodology, illustrating differences but not elucidating their origin. The extracted relaxation times reflect the combined effect of all solutes (antibody, buffer components, etc.) on the solvent (water).
Assuntos
Produtos Biológicos , Imageamento por Ressonância Magnética , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância MagnéticaRESUMO
In an effort to understand the effect of N-alkylation of triarylimidazoles on Tie2 inhibition, ortho-substituted C-2 aryl analogs were synthesized to investigate the effect of different torsion angles on potency. This exercise resulted in the identification of a potent and selective tetrasubstituted imidazole that was efficacious in an animal model of angiogenesis.
Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Receptor TIE-2/antagonistas & inibidores , Imidazóis/química , Concentração Inibidora 50 , Metilação , Modelos Moleculares , Conformação Molecular , Inibidores de Proteínas Quinases/química , Receptor TIE-2/química , Receptor TIE-2/metabolismo , Sensibilidade e Especificidade , Relação Estrutura-AtividadeRESUMO
This communication details the evolution of the screening lead SB-203580, a known CSBP/p38 kinase inhibitor, into a potent and selective Tie2 tyrosine kinase inhibitor. The optimized compound 5 showed efficacy in an in vivo model of angiogenesis and a MOPC-315 plasmacytoma xenograft model.