ABSTRACT
In this manuscript, we report the discovery of the substituted 2-trifluoromethyl-2H-benzopyran-3-carboxylic acids as a novel series of potent and selective cyclooxygenase-2 (COX-2) inhibitors. We provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data. The challenge of a surprisingly long half-life (t(1/2)=360 h) of the first clinical candidate 1 and human t(1/2) had been difficult to predict based on allometric scaling for this class of highly ppb compounds. We used a microdose strategy which led to the discovery of clinical agents 18c-(S), 29b-(S), and 34b-(S) with human half-life of 57, 13, and 11 h.
Subject(s)
Benzopyrans/pharmacokinetics , Cyclooxygenase 2 Inhibitors/chemistry , Drug Discovery/methods , Benzopyrans/chemistry , Carboxylic Acids , Cyclooxygenase 2 Inhibitors/pharmacokinetics , Dose-Response Relationship, Drug , Half-Life , Humans , Structure-Activity RelationshipABSTRACT
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.
