ABSTRACT
A computer-aided drug design strategy leads to the identification of a new class of p38 inhibitors based on the 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) scaffold. The tolyl triazole amides provided a potent platform amenable to optimization. Further exploration leads to compounds with greater than 100-fold improvement in binding affinity to p38. Derivatives prepared to alter the physicochemical properties produced inhibitors with IC(50)'s in human whole blood as low as 83 nM.
Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Binding Sites , Computer-Aided Design , Enzyme Inhibitors/blood , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Structure-Activity Relationship , Triazoles/blood , Triazoles/chemistryABSTRACT
[structure: see text] A model system has been used to study the interactions of dipole-containing aromatic systems with oxidized and reduced flavin. Ab initio computational and experimental studies show that dipole orientation within the host is a critical determinant for recognition and redox behavior of the flavin guest.
