RESUMEN
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.
Asunto(s)
Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Animales , Células CHO , Quimiotaxis de Leucocito/efectos de los fármacos , Simulación por Computador , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Indicadores y Reactivos , Proteína Quinasa de Distrofia Miotónica , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Receptores CCR8 , Relación Estructura-Actividad , Células Th2/efectos de los fármacosRESUMEN
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.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Benzoxazinas/síntesis química , Receptores de Glucocorticoides/agonistas , Tetrahidronaftalenos/síntesis química , Administración Tópica , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Benzoxazinas/química , Benzoxazinas/farmacología , Unión Competitiva , Línea Celular , Dexametasona/farmacología , Humanos , Hipersensibilidad Tardía/tratamiento farmacológico , Ratones , Modelos Moleculares , Ensayo de Unión Radioligante , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/genética , Estereoisomerismo , Relación Estructura-Actividad , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacología , Transcripción Genética/efectos de los fármacos , Activación Transcripcional/efectos de los fármacosRESUMEN
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.