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1.
Bioorg Med Chem Lett ; 22(7): 2407-10, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22406115

RESUMO

Structural modification of a series of dual LXRα/ß agonists led to the identification of a new class of LXRß partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRß with a reversed orientation compared to 1.


Assuntos
Receptores Nucleares Órfãos/agonistas , Isoformas de Proteínas/agonistas , Pirróis/síntese química , Sítios de Ligação , Células CACO-2 , Cristalografia por Raios X , Genes Reporter , Células HEK293 , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos/química , Ligação Proteica , Isoformas de Proteínas/química , Pirróis/farmacologia , Relação Estrutura-Atividade , Transfecção
2.
Bioorg Med Chem Lett ; 22(18): 5966-70, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22901900

RESUMO

The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/ß) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.


Assuntos
Descoberta de Drogas , Receptores Nucleares Órfãos/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Ligantes , Receptores X do Fígado , Masculino , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Benzenossulfonamidas
3.
J Biol Chem ; 283(14): 9168-76, 2008 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-18263587

RESUMO

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) plays central roles in adipogenesis and glucose homeostasis and is the molecular target for the thiazolidinedione (TZD) class of antidiabetic drugs. Activation of PPARgamma by TZDs improves insulin sensitivity; however, this is accompanied by the induction of several undesirable side effects. We have identified a novel synthetic PPARgamma ligand, T2384, to explore the biological activities associated with occupying different regions of the receptor ligand-binding pocket. X-ray crystallography studies revealed that T2384 can adopt two distinct binding modes, which we have termed "U" and "S", interacting with the ligand-binding pocket of PPARgamma primarily via hydrophobic contacts that are distinct from full agonists. The different binding modes occupied by T2384 induced distinct patterns of coregulatory protein interaction with PPARgamma in vitro and displayed unique receptor function in cell-based activity assays. We speculate that these unique biochemical and cellular activities may be responsible for the novel in vivo profile observed in animals treated systemically with T2384. When administered to diabetic KKAy mice, T2384 rapidly improved insulin sensitivity in the absence of weight gain, hemodilution, and anemia characteristics of treatment with rosiglitazone (a TZD). Moreover, upon coadministration with rosiglitazone, T2384 was able to antagonize the side effects induced by rosiglitazone treatment alone while retaining robust effects on glucose disposal. These results are consistent with the hypothesis that interactions between ligands and specific regions of the receptor ligand-binding pocket might selectively trigger a subset of receptor-mediated biological responses leading to the improvement of insulin sensitivity, without eliciting less desirable responses associated with full activation of the receptor. We suggest that T2384 may represent a prototype for a novel class of PPARgamma ligand and, furthermore, that molecules sharing some of these properties would be useful for treatment of type 2 diabetes.


Assuntos
Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Benzotiazóis/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Sulfonamidas/farmacologia , Adipócitos/patologia , Animais , Benzotiazóis/química , Benzotiazóis/uso terapêutico , Sítios de Ligação , Células Cultivadas , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Ligantes , Camundongos , Modelos Moleculares , PPAR gama/química , PPAR gama/metabolismo , Rosiglitazona , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Aumento de Peso/efeitos dos fármacos
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