RESUMO
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.
Assuntos
Fenilpropionatos/síntese química , Piridinas/síntese química , Receptores dos Hormônios Tireóideos/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Ligantes , Modelos Moleculares , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Piridinas/química , Piridinas/farmacologia , Ratos , Receptores alfa dos Hormônios Tireóideos/antagonistas & inibidores , Receptores beta dos Hormônios Tireóideos/antagonistas & inibidores , Receptores beta dos Hormônios Tireóideos/química , Ativação Transcricional/efeitos dos fármacosRESUMO
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.
Assuntos
Receptores alfa dos Hormônios Tireóideos/antagonistas & inibidores , Receptores beta dos Hormônios Tireóideos/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , Éteres/síntese química , Éteres/química , Éteres/farmacologia , Genes Reporter , Humanos , Ligantes , Modelos Moleculares , Fenóis/química , Estrutura Secundária de Proteína , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Receptores alfa dos Hormônios Tireóideos/química , Receptores beta dos Hormônios Tireóideos/químicaRESUMO
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.
Assuntos
Benzilaminas/síntese química , Hipoglicemiantes/síntese química , Receptores de Glucocorticoides/antagonistas & inibidores , Sulfonamidas/síntese química , Fosfatase Alcalina/biossíntese , Fosfatase Alcalina/genética , Animais , Benzilaminas/efeitos adversos , Benzilaminas/farmacologia , Células Cultivadas , Cricetinae , Cricetulus , Dexametasona/farmacologia , Feminino , Genes Reporter , Glucocorticoides/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Camundongos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Gravidez , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Ativação Transcricional/efeitos dos fármacos , Tirosina Transaminase/biossíntese , Útero/efeitos dos fármacosRESUMO
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.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/síntese química , Fígado/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Ácidos e Sais Biliares/química , Sítios de Ligação , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Células CHO , Células Cultivadas , Simulação por Computador , Cricetinae , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Glucose/biossíntese , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Camundongos , Modelos Moleculares , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Glucocorticoides/química , Glucocorticoides/farmacocinética , Fígado/metabolismo , Mifepristona/análogos & derivados , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Glucocorticoides/síntese química , Ratos , Ratos EndogâmicosRESUMO
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.
Assuntos
Aminoácidos/farmacologia , Mimetismo Molecular , Éteres Fenílicos/farmacologia , Fenilacetatos/farmacologia , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Aminoácidos/química , Animais , Células CHO , Colesterol na Dieta/administração & dosagem , Cricetinae , Cricetulus , Ligantes , Ensaio Radioligante , Ratos , Receptores dos Hormônios Tireóideos/metabolismoRESUMO
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.
Assuntos
Indóis/química , Indóis/farmacologia , Receptores beta dos Hormônios Tireóideos/agonistas , Receptores beta dos Hormônios Tireóideos/metabolismo , Animais , Cristalografia por Raios X , Ciclização , Humanos , Indóis/metabolismo , Concentração Inibidora 50 , Ligantes , Estrutura Molecular , Ratos , Especificidade por Substrato , Receptores beta dos Hormônios Tireóideos/química , Tiroxina/síntese química , Tiroxina/químicaRESUMO
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.
Assuntos
Amidas/farmacologia , Receptores beta dos Hormônios Tireóideos/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Éteres Fenílicos/química , Fenilacetatos/química , Conformação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Receptores alfa dos Hormônios Tireóideos/efeitos dos fármacos , Hormônios Tireóideos/química , Tri-Iodotironina/químicaRESUMO
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.
Assuntos
Ácidos e Sais Biliares/química , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Humanos , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Estrutura Molecular , Ratos , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Naftalenos/química , Receptores dos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/metabolismo , Modelos Moleculares , Relação Estrutura-Atividade , Hormônios Tireóideos/químicaRESUMO
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.
Assuntos
Glicemia/metabolismo , Ácidos Cólicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Estrona/análogos & derivados , Glucose/metabolismo , Fígado/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Células 3T3 , Adipócitos/metabolismo , Animais , Biotransformação/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ácidos Cólicos/metabolismo , Diabetes Mellitus Tipo 2/sangue , Cães , Sinergismo Farmacológico , Estrona/metabolismo , Estrona/farmacologia , Glucocorticoides/farmacologia , Glutamato-Amônia Ligase/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Obesidade/metabolismo , Prednisolona/farmacologia , Ratos , Ratos Zucker , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rosiglitazona , Tiazolidinedionas/farmacologia , Tirosina Transaminase/metabolismoRESUMO
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.
Assuntos
Ácidos e Sais Biliares/química , Receptores de Glucocorticoides/efeitos dos fármacos , Animais , Ácidos e Sais Biliares/farmacocinética , Disponibilidade Biológica , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Receptores de Glucocorticoides/efeitos dos fármacos , Animais , Compostos de Benzil , Humanos , Ratos , Relação Estrutura-Atividade , SulfonamidasRESUMO
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).
Assuntos
Receptores de Glucocorticoides/efeitos dos fármacos , Humanos , Ligantes , Ligação Proteica , Receptores de Glucocorticoides/metabolismoRESUMO
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.
Assuntos
Sistemas de Liberação de Medicamentos , Glucuronídeos/metabolismo , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/farmacologia , Fígado/efeitos dos fármacos , Mifepristona/administração & dosagem , Mifepristona/farmacologia , Receptores de Glucocorticoides/antagonistas & inibidores , Administração Oral , Fosfatase Alcalina/antagonistas & inibidores , Animais , Ligação Competitiva/efeitos dos fármacos , Dexametasona/farmacocinética , Circulação Êntero-Hepática , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glucocorticoides/farmacocinética , Glucuronídeos/farmacocinética , Antagonistas de Hormônios/farmacocinética , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Injeções Intravenosas , Microssomos Hepáticos/metabolismo , Mifepristona/farmacocinética , Compostos de Amônio Quaternário , Ratos , Ratos Sprague-Dawley , Tirosina Transaminase/antagonistas & inibidoresRESUMO
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.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Receptores de Glucocorticoides/efeitos dos fármacos , Meia-Vida , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/químicaRESUMO
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.