RESUMEN
Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.
Asunto(s)
Descubrimiento de Drogas , Glucocorticoides/síntesis química , Metanol/química , Receptores de Glucocorticoides/agonistas , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Artritis/tratamiento farmacológico , Sitios de Unión , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glucocorticoides/química , Glucocorticoides/farmacología , Humanos , Concentración 50 Inhibidora , Metanol/síntesis química , Metanol/farmacología , Ratones , Modelos Moleculares , Estructura Molecular , Prednisolona/química , Prednisolona/farmacología , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.
Asunto(s)
Glucocorticoides/química , Glucocorticoides/farmacología , Indoles/química , Indoles/farmacología , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/metabolismo , Animales , Células HeLa , Humanos , Ratones , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
An effort aimed at exploring structural diversity in the N-pyrazole-N'-naphthylurea class of p38 kinase inhibitors led to the synthesis and characterization of N-phenyl-N'-naphthylureas. Examples of these compounds displayed excellent inhibition of TNF-alpha production in vitro, as well as efficacy in a mouse model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a sulfonamide functionality in defining inhibitor potency.
Asunto(s)
2-Naftilamina/análogos & derivados , Inhibidores de Proteínas Quinasas/farmacología , Urea/análogos & derivados , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , 2-Naftilamina/química , Animales , Química Orgánica/métodos , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Concentración 50 Inhibidora , Lipopolisacáridos/metabolismo , Ratones , Modelos Químicos , Estructura Molecular , Factor de Necrosis Tumoral alfa/metabolismo , Urea/químicaRESUMEN
Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.
Asunto(s)
Modelos Moleculares , Inhibidores de Proteínas Quinasas/síntesis química , Sulfonamidas/síntesis química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/química , Animales , Sitios de Unión , Disponibilidad Biológica , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Lipopolisacáridos/farmacología , Masculino , Ratones , Niacinamida/análogos & derivados , Niacinamida/síntesis química , Niacinamida/química , Niacinamida/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Tiofenos/síntesis química , Tiofenos/química , Tiofenos/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
We report on a series of N-pyrazole, N'-aryl ureas and their mode of binding to p38 mitogen activated protein kinase. Importantly, a key binding domain that is distinct from the adenosine 5'-triphoshate (ATP) binding site is exposed when the conserved activation loop, consisting in part of Asp168-Phe169-Gly170, adopts a conformation permitting lipophilic and hydrogen bonding interactions between this class of inhibitors and the protein. We describe the correlation of the structure-activity relationships and crystallographic structures of these inhibitors with p38. In addition, we incorporated another binding pharmacophore that forms a hydrogen bond at the ATP binding site. This modification affords significant improvements in binding, cellular, and in vivo potencies resulting in the selection of 45 (BIRB 796) as a clinical candidate for the treatment of inflammatory diseases.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Inhibidores Enzimáticos/síntesis química , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Naftalenos/síntesis química , Pirazoles/síntesis química , Urea/análogos & derivados , Urea/síntesis química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Unión Competitiva , Línea Celular , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Fluorescencia , Humanos , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Naftalenos/química , Naftalenos/farmacología , Unión Proteica , Pirazoles/química , Pirazoles/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesis , Urea/química , Urea/farmacología , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH(2) interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degrees C translating into K(d) values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Naftalenos/síntesis química , Pirazoles/síntesis química , Urea/análogos & derivados , Urea/síntesis química , Animales , Línea Celular , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Ensayo de Inmunoadsorción Enzimática , Calefacción , Humanos , Técnicas In Vitro , Ligandos , Lipopolisacáridos/farmacología , Ratones , Proteína Quinasa 14 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/química , Naftalenos/química , Unión Proteica , Desnaturalización Proteica , Pirazoles/química , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis , Urea/químicaRESUMEN
Syntheses and structure-activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds (R)-16 and (R)-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Piridinas/síntesis química , Pirroles/síntesis química , Receptores de Glucocorticoides/agonistas , Esteroides/química , Tejido Adiposo/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Aromatasa/biosíntesis , Aromatasa/genética , Inhibidores de la Aromatasa/farmacología , Artritis Experimental/tratamiento farmacológico , Disponibilidad Biológica , Células Cultivadas , Inducción Enzimática , Femenino , Humanos , Enlace de Hidrógeno , Insulina/sangre , Interleucina-1/farmacología , Interleucina-6/antagonistas & inhibidores , Interleucina-6/biosíntesis , Interleucina-6/genética , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Piridinas/efectos adversos , Piridinas/farmacología , Pirroles/efectos adversos , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Activación TranscripcionalRESUMEN
Discovery of the pyrazole-naphthyl urea class of p38 MAP kinase inhibitors typified by the clinical candidate BIRB 796 has encouraged further exploration of this particular scaffold. Modification to the part of the inhibitor that occupies the adenine/ATP binding site has resulted in a new way to obtain potent inhibitors that possess favorable in vitro and in vivo properties.