RESUMEN
Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/síntesis química , Piperazinas/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Adamantano/farmacocinética , Animales , Línea Celular , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Piperazinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Adamantano/síntesis química , Alquilación , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Éteres/síntesis química , Éteres/farmacología , Semivida , Humanos , Indicadores y Reactivos , Ratones , Ratones Noqueados , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Modelos MolecularesRESUMEN
Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/síntesis química , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Tejido Adiposo/enzimología , Animales , Encéfalo/enzimología , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Humanos , Indicadores y Reactivos , Hígado/enzimología , Ratones , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Libraries of mifepristone analogs, MP-Acids, were designed and synthesized to increase the chances of identifying GR antagonists that possess liver-selective pharmacological profiles. MP-Acids were uniformly potent GR antagonists in binding and in cell-based functional assays. A high throughput pharmacokinetic selection strategy that employs the cassette dosing of MP-Acids was developed to identify liver-targeting compounds. Thus, resource-intensive in vivo assays to measure liver-selective pharmacology were enriched with GR antagonists that achieve high concentrations in the liver.
Asunto(s)
Glucocorticoides/química , Glucocorticoides/farmacocinética , Hígado/metabolismo , Mifepristona/análogos & derivados , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Glucocorticoides/síntesis química , Ratas , Ratas EndogámicasRESUMEN
A series of potent and selective adamantane aminoamide 11-beta-HSD-1 inhibitors has been optimized. Chemically these studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction. Structure-activity relationship studies resulted in the discovery of dual human and mouse 11-beta-HSD-1 potent and selective inhibitors like adamantane 11 and related compounds with high metabolic stability and robust pharmacokinetic profiles.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Adamantano/farmacología , Cianuros/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Adamantano/química , Adamantano/farmacocinética , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of potent steroidal glucocorticoid receptor antagonists has been discovered. After conjugation to cholic acid, the compounds retained an affinity for GR in vitro and had modest in vivo efficacy.
Asunto(s)
Ácidos y Sales Biliares/química , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Humanos , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Estructura Molecular , Ratas , Receptores de Glucocorticoides/metabolismo , Relación Estructura-ActividadRESUMEN
High throughput screening efforts have identified a novel class of dichloroaniline amide 11beta-HSD1 inhibitors. SAR studies initiated from dichloroaniline 4 focused on retaining the potency and selectivity profile of the lead.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Síndrome Metabólico/tratamiento farmacológico , Carbenoxolona/química , Carbenoxolona/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Conformación Molecular , Piperazinas/química , Piperazinas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
A series of metabolically stable adamantane amide 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity and good pharmacokinetic and pharmacodynamic profiles.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Adamantano/química , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replacements have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11beta-HSD1 potency and 11beta-HSD2 selectivity.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Adamantano/química , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of metabolically stable butyrolactam 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Lactamas/farmacología , Administración Oral , Animales , Humanos , Lactamas/administración & dosificación , Lactamas/síntesis química , Lactamas/farmacocinética , Síndrome Metabólico/tratamiento farmacológico , RatonesRESUMEN
Much has been learned about the consequences of glucocorticoid receptor antagonism by studying steroidal active antagonists such as RU-38486 (1). In the liver glucocorticoid receptor antagonism suppresses hepatic glucose production decreasing plasma glucose levels; however, extrahepatic antagonism produces several undesirable side effects including activation of the hypothalamic pituitary adrenal axis. A series of nonsteroidal passive N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamide glucocorticoid receptor modulators was discovered. Liver selective and systemically available members of this series were found and characterized in diabetes and side effect rodent models. A highly liver selective member of this series, acid 14, shows efficacy in the ob/ob model of diabetes. It lowers plasma glucose, cholesterol, and free fatty acid concentrations and reduces the rate of body weight gain. The structurally related systemically available passive modulator 12 lowers glucose, HbA(1c), triglyceride, free fatty acid, and cholesterol levels. Interestingly, it did not acutely activate the hypothalamic pituitary adrenal axis in unstressed CD-1 mice or have the abortive effects observed with 1. These results indicate that passive GR antagonists may have utility as antidiabetic agents.
Asunto(s)
Bencilaminas/síntesis química , Hipoglucemiantes/síntesis química , Receptores de Glucocorticoides/antagonistas & inhibidores , Sulfonamidas/síntesis química , Fosfatasa Alcalina/biosíntesis , Fosfatasa Alcalina/genética , Animales , Bencilaminas/efectos adversos , Bencilaminas/farmacología , Células Cultivadas , Cricetinae , Cricetulus , Dexametasona/farmacología , Femenino , Genes Reporteros , Glucocorticoides/farmacología , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Ratones , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Embarazo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/genética , Sulfonamidas/efectos adversos , Sulfonamidas/farmacología , Activación Transcripcional/efectos de los fármacos , Tirosina Transaminasa/biosíntesis , Útero/efectos de los fármacosRESUMEN
Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.
Asunto(s)
Glucemia/metabolismo , Ácidos Cólicos/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Estrona/análogos & derivados , Glucosa/metabolismo , Hígado/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Células 3T3 , Adipocitos/metabolismo , Animales , Biotransformación/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Ácidos Cólicos/metabolismo , Diabetes Mellitus Tipo 2/sangre , Perros , Sinergismo Farmacológico , Estrona/metabolismo , Estrona/farmacología , Glucocorticoides/farmacología , Glutamato-Amoníaco Ligasa/metabolismo , Hipoglucemiantes/farmacología , Masculino , Ratones , Obesidad/metabolismo , Prednisolona/farmacología , Ratas , Ratas Zucker , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rosiglitazona , Tiazolidinedionas/farmacología , Tirosina Transaminasa/metabolismoRESUMEN
Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/síntesis química , Hígado/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Ácidos y Sales Biliares/química , Sitios de Unión , Hidrocarburos Aromáticos con Puentes/química , Hidrocarburos Aromáticos con Puentes/farmacología , Células CHO , Células Cultivadas , Simulación por Computador , Cricetinae , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Tipo 2/sangre , Glucosa/biosíntesis , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Ratones , Modelos Moleculares , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis, activity, metabolic stability, and pharmacokinetics of steroidal and nonsteroidal glucocorticoid receptor modulator-statin hybrids is reported. Potent steroidal antagonist-statin hybrids like 22 (h-GR binding IC(50)=7 nM) and nonsteroidal modulator hybrids like 16 (h-GR binding IC(50)=2 nM) were discovered. Appending a 'statin'-like diol-acid group to the modulators dramatically improved metabolic stability (and in some cases hepatocyte activity), but did not impart hepatoselectivity.