RESUMEN
A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.
Asunto(s)
Descubrimiento de Drogas , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/química , Pirroles/química , Administración Oral , Animales , Ensayo de Inmunoadsorción Enzimática , Humanos , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Conformación Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-Actividad , Distribución TisularRESUMEN
A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.
Asunto(s)
Amidas/farmacología , Receptores de Glucocorticoides/agonistas , Amidas/química , Animales , Modelos Moleculares , RatasRESUMEN
A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.
Asunto(s)
Antracenos/farmacología , Descubrimiento de Drogas , Receptores de Glucocorticoides/metabolismo , Antracenos/química , Línea Celular , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Glucocorticoides/química , Glucocorticoides/farmacología , Humanos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/fisiología , Relación Estructura-ActividadRESUMEN
Modification of the cladinose C-4" position via manipulation of the corresponding keto derivatives afforded two stereochemically pure series of compounds. The synthesis and structure determination of these compounds is described within. The in vitro and in vivo biological activity of this novel series of C-4" modified macrolides is also described.