ABSTRACT
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.
Subject(s)
Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Animals , CHO Cells , Chemotaxis, Leukocyte/drug effects , Computer Simulation , Cricetinae , Cricetulus , Drug Evaluation, Preclinical , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Indicators and Reagents , Myotonin-Protein Kinase , Protein Serine-Threonine Kinases/drug effects , Receptors, CCR8 , Structure-Activity Relationship , Th2 Cells/drug effectsABSTRACT
The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzoxazines/chemical synthesis , Receptors, Glucocorticoid/agonists , Tetrahydronaphthalenes/chemical synthesis , Administration, Topical , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzoxazines/chemistry , Benzoxazines/pharmacology , Binding, Competitive , Cell Line , Dexamethasone/pharmacology , Humans , Hypersensitivity, Delayed/drug therapy , Mice , Models, Molecular , Radioligand Assay , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Glucocorticoid/genetics , Stereoisomerism , Structure-Activity Relationship , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacology , Transcription, Genetic/drug effects , Transcriptional Activation/drug effectsABSTRACT
Structurally related glucocorticoid receptor (GR) binders were docked into the GR active site to select the binding mode closest to the true docking mode. This process, termed an "agreement docking method", led to the design of tetrahydronaphthalene 9. The method was validated by the syntheses of 9 and related analogues, which are potent binders of GR. 15a is a partial agonist while 9e and 15a are micromolar antagonists in a mouse mammary tumor virus transactivation assay.
