ABSTRACT
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).
Subject(s)
Biological Products , Magnetic Resonance Imaging , Chromatography, High Pressure Liquid , Magnetic Resonance SpectroscopyABSTRACT
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.
Subject(s)
Imidazoles/chemical synthesis , Imidazoles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Receptor, TIE-2/antagonists & inhibitors , Imidazoles/chemistry , Inhibitory Concentration 50 , Methylation , Models, Molecular , Molecular Conformation , Protein Kinase Inhibitors/chemistry , Receptor, TIE-2/chemistry , Receptor, TIE-2/metabolism , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
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.
