RESUMO
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
Based on the concept of 'indirect antagonism' of nuclear receptors, a series of thyroid hormone receptor (TR) antagonists were prepared with improved affinity compared with what was previously described. The results of a binding assay for the human TR and reporter cell assay revealed, within this series, that an m-bromobenzoyl substituent (11f) was optimal in terms of affinity and antagonist activity. Compared with already reported TR antagonists, their affinities are within the same range, thus potentially representing useful approach to novel and high-affinity TR-antagonists.
Assuntos
Brometos/síntese química , Química Farmacêutica/métodos , Receptores alfa dos Hormônios Tireóideos/antagonistas & inibidores , Receptores beta dos Hormônios Tireóideos/antagonistas & inibidores , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Ligantes , Modelos Químicos , Conformação Molecular , Ligação Proteica , Isoformas de Proteínas , Relação Estrutura-Atividade , Receptores alfa dos Hormônios Tireóideos/química , Receptores beta dos Hormônios Tireóideos/química , Ativação TranscricionalRESUMO
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
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
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.