ABSTRACT
Series of aminopyridinecarboxamide-based inhibitors were synthesized and tested against human recombinant IKK-2 and in IL-1beta stimulated synovial fibroblasts. The 2-amino-5-chloropyridine-4-carboxamides were identified as the most potent inhibitors with improved cellular activity.
Subject(s)
Aminopyrine/chemistry , Aminopyrine/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Interleukin-1beta/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Amino Acid Sequence , Arthritis, Rheumatoid/drug therapy , Fibroblasts/drug effects , Fibroblasts/immunology , Humans , I-kappa B Kinase/metabolism , I-kappa B Proteins/chemistry , Interleukin-1beta/metabolism , Joint Capsule/cytology , Molecular Sequence Data , Structure-Activity RelationshipABSTRACT
A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.