RESUMEN
Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.
Asunto(s)
Aminoácidos/farmacología , Imitación Molecular , Éteres Fenílicos/farmacología , Fenilacetatos/farmacología , Receptores de Hormona Tiroidea/efectos de los fármacos , Aminoácidos/química , Animales , Células CHO , Colesterol en la Dieta/administración & dosificación , Cricetinae , Cricetulus , Ligandos , Ensayo de Unión Radioligante , Ratas , Receptores de Hormona Tiroidea/metabolismoRESUMEN
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 new high-affinity thyroid hormone antagonist 6 with druglike properties was designed and synthesized. The compound behaved as an antagonist in a cell transactivation assay, and in a first in vivo experiment in rats.
Asunto(s)
Fenilpropionatos/síntesis química , Piridinas/síntesis química , Receptores de Hormona Tiroidea/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Ligandos , Modelos Moleculares , Fenilpropionatos/química , Fenilpropionatos/farmacología , Piridinas/química , Piridinas/farmacología , Ratas , Receptores alfa de Hormona Tiroidea/antagonistas & inhibidores , Receptores beta de Hormona Tiroidea/antagonistas & inhibidores , Receptores beta de Hormona Tiroidea/química , Activación Transcripcional/efectos de los fármacosRESUMEN
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
Based on the examination of the crystal structure of rat TRbeta complexed with 3,5,3'-triiodo-l-thyronine (2) a novel TRbeta-selective indole derivative 6b was prepared and tested in vitro. This compound was found to be 14 times selective for TRbeta over TRalpha in binding and its beta-selectivity could be rationalized through the comparison of the X-ray crystallographic structures of 6b complexed with TRalpha and TRbeta.
Asunto(s)
Indoles/química , Indoles/farmacología , Receptores beta de Hormona Tiroidea/agonistas , Receptores beta de Hormona Tiroidea/metabolismo , Animales , Cristalografía por Rayos X , Ciclización , Humanos , Indoles/metabolismo , Concentración 50 Inhibidora , Ligandos , Estructura Molecular , Ratas , Especificidad por Sustrato , Receptores beta de Hormona Tiroidea/química , Tiroxina/síntesis química , Tiroxina/químicaRESUMEN
Based on the examination of the X-ray crystallographic structures of the LBD of TRalpha and TRbeta in complex with KB-141 (2), a number of novel 4'-hydroxy bioisosteric thyromimetics were prepared. Optimal affinity and beta-selectivity (33 times), was found with a medium-sized alkyl-substituted amido group; iso-butyl (12c). It can be concluded that bioisosteric replacements of the 4'-hydroxy position represent a new promising class of TRbeta-selective synthetic thyromimetics.
Asunto(s)
Amidas/farmacología , Receptores beta de Hormona Tiroidea/efectos de los fármacos , Amidas/síntesis química , Amidas/química , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Éteres Fenílicos/química , Fenilacetatos/química , Conformación Proteica , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Receptores alfa de Hormona Tiroidea/efectos de los fármacos , Hormonas Tiroideas/química , Triyodotironina/químicaRESUMEN
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
High affinity thyromimetics containing a novel phenyl-naphthylene core are reported. The functionalized core is readily accessible via a Suzuki coupling protocol. Examples of this new class of TR ligands have sub-nanomolar binding affinities for the TRbeta receptor and low to modest selectivity for TRbeta. They also exhibit an SAR that diverges from other thyromimetics that are based on the diaryl ether core found in 3,5,3'-triiodothyronine.
Asunto(s)
Naftalenos/química , Receptores de Hormona Tiroidea/metabolismo , Hormonas Tiroideas/metabolismo , Modelos Moleculares , Relación Estructura-Actividad , Hormonas Tiroideas/químicaRESUMEN
Based on the recently described concept of "indirect antagonism" of nuclear receptors, a series of thyroid hormone receptor (TR) antagonists were prepared, in which the outer ring of a thyromimetic was replaced with alkyl chains of variable length and branch. The results of a binding assay for the human TR and reporter cell assay revealed, within this series, a positive correlation between increasing bulk of the alkyl group and affinity to TRs. Compared with already reported TR antagonists, their affinities are within the same range, thus potentially representing a useful approach to novel and high affinity TR-antagonists.
Asunto(s)
Receptores alfa de Hormona Tiroidea/antagonistas & inhibidores , Receptores beta de Hormona Tiroidea/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Éteres/síntesis química , Éteres/química , Éteres/farmacología , Genes Reporteros , Humanos , Ligandos , Modelos Moleculares , Fenoles/química , Estructura Secundaria de Proteína , Ensayo de Unión Radioligante , Ratas , Relación Estructura-Actividad , Receptores alfa de Hormona Tiroidea/química , Receptores beta de Hormona Tiroidea/químicaRESUMEN
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 optimization of a series of nonsteroidal glucocorticoid modulators is reported. Potent selective GR ligands that have improved metabolic stability were discovered typified by the subnanomolar acid 12 (GR binding IC(50)=0.6 nM).
Asunto(s)
Receptores de Glucocorticoides/efectos de los fármacos , Humanos , Ligandos , Unión Proteica , Receptores de Glucocorticoides/metabolismoRESUMEN
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.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/síntesis química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Receptores de Glucocorticoides/efectos de los fármacos , Semivida , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/químicaRESUMEN
Bile acid conjugates of a selective nonsteroidal glucocorticoid receptor modulator were prepared and evaluated. Potent GR binding conjugates that showed improved metabolic stability were discovered. However, cellular potency and pharmacokinetics were not substantially improved.
Asunto(s)
Ácidos y Sales Biliares/química , Receptores de Glucocorticoides/efectos de los fármacos , Animales , Ácidos y Sales Biliares/farmacocinética , Disponibilidad Biológica , Ratas , Ratas Sprague-DawleyRESUMEN
A set of thyromimetics having improved selectivity for TR-beta1 were prepared by replacing the 3'-isopropyl group of 2 and 3 with substituents having increased steric bulk. From this limited SAR study, the most potent and selective compounds identified were derived from 2 and contained a 3'-phenyl moiety bearing small hydrophobic groups meta to the biphenyl link. X-ray crystal data of 15c complexed with TR-beta1 LBD shows methionine 442 to be displaced by the bulky R3' phenyl ethyl amide side chain. Movement of this amino acid side chain provides an expanded pocket for the bulky side chain while the ligand-receptor complex retains full agonist activity.
Asunto(s)
Receptores beta de Hormona Tiroidea/metabolismo , Hormonas Tiroideas/química , Triyodotironina/química , 2-Propanol/química , Aminoácidos/química , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Diseño de Fármacos , Concentración 50 Inhibidora , Ligandos , Relación Estructura-Actividad , Receptores beta de Hormona Tiroidea/efectos de los fármacos , Hormonas Tiroideas/metabolismo , Hormonas Tiroideas/farmacología , Triyodotironina/metabolismo , Triyodotironina/farmacologíaRESUMEN
A new class of selective nonsteroidal glucocorticoid receptor modulators typified by N-[3-[benzyl-(4-chloro-2-fluoro-benzyl)-amino]-2-methyl-phenyl]-methanesulfonamide 19 has been discovered.
Asunto(s)
Receptores de Glucocorticoides/efectos de los fármacos , Animales , Compuestos de Bencilo , Humanos , Ratas , Relación Estructura-Actividad , SulfonamidasRESUMEN
A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.