ABSTRACT
A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.
Subject(s)
Anti-Inflammatory Agents/chemistry , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Quantitative Structure-Activity Relationship , Quinoxalines/chemistry , Quinoxalines/pharmacokinetics , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Biological Availability , Cytokines/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Female , Hydrogen Bonding , Inhibitory Concentration 50 , Mice , Mice, Inbred C57BL , Models, Molecular , Pyrazines/chemistry , Pyrazines/pharmacology , Quinoxalines/pharmacology , src-Family Kinases/antagonists & inhibitorsABSTRACT
A series of anilino(imidazoquinoxaline) analogues bearing solubilizing side chains at the 6- and 7-positions of the fused phenyl ring has been prepared and evaluated for inhibition against Lck enzyme and of T-cell proliferation. Significant improvement of the cellular activity was achieved over the initial lead, compound 2.
