RESUMO
A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.
Assuntos
Anti-Hipertensivos/síntese química , Indóis/síntese química , Antagonistas de Receptores de Mineralocorticoides , Sulfonamidas/síntese química , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Cristalografia por Raios X , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
The design and synthesis of a novel piperidine series of farnesyltransferase (FTase) inhibitors with reduced potential for metabolic glucuronidation are described. The various substitution and exchange of the phenyl group at the C-2 position of the previously described 2-(4-hydroxy)phenyl-3-nitropiperidine 1a (FTase IC(50)=5.4nM) resulted in metabolically stable compounds with potent FTase inhibition (14a IC(50)=4.3nM, 20a IC(50)=3.0nM, and 50a IC(50)=16nM). Molecular modeling studies of these compounds complexed with FTase and farnesyl pyrophosphate are also described.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Glucuronídeos/metabolismo , Piperidinas/síntese química , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Prenilação de Proteína , Ratos , Relação Estrutura-AtividadeRESUMO
Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARalpha and RXR:PPARgamma, but not RXR:RARalpha, RXR:LXRalpha, RXR:LXRbeta, or RXR:FXRalpha. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Graxos Insaturados/administração & dosagem , Hipoglicemiantes/administração & dosagem , Obesidade/tratamento farmacológico , Éteres Fenílicos/administração & dosagem , Receptores X de Retinoides/agonistas , Tiazolidinedionas/administração & dosagem , Análise de Variância , Animais , Apolipoproteína A-I/genética , Apolipoproteína A-I/fisiologia , Área Sob a Curva , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Hipoglicemiantes/uso terapêutico , Camundongos , Camundongos Transgênicos , Obesidade/sangue , Obesidade/complicações , PPAR gama/agonistas , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Receptores X de Retinoides/metabolismo , Rosiglitazona , Estatísticas não Paramétricas , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Glândula Tireoide/efeitos dos fármacos , Triglicerídeos/sangueRESUMO
Syntheses and SAR studies of 3,3-bisaryloxindole analogues provided potent mineralocorticoid receptor (MR) antagonists that were selective over other steroid nuclear hormone receptors.
Assuntos
Indóis/farmacologia , Antagonistas de Receptores de Mineralocorticoides , Humanos , Ensaio RadioliganteRESUMO
The synthesis and in vitro characterization of novel RXR-selective ligands possessing various substituted 1-benzofuran or 1-benzothiophene moieties are described.
Assuntos
Desenho de Fármacos , Receptores do Ácido Retinoico/metabolismo , Fatores de Transcrição/metabolismo , Tretinoína/análogos & derivados , Tretinoína/metabolismo , Ligação Proteica/fisiologia , Receptores X de Retinoides , Relação Estrutura-AtividadeRESUMO
New RXR-selective modulators possessing a 6-fluoro trienoic acid moiety (6Z olefin) or a fluorinated/heterocyclic-substituted benzene core ring, were synthesized in an expedient and selective way. A subset of these compounds was evaluated for their metabolic properties (exposure in IRC male mice) and show a dramatic increase of exposure compared to our reference compound, 3 (LG101506).
Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacologia , Receptores do Ácido Retinoico/fisiologia , Fatores de Transcrição/fisiologia , Animais , Ligação Competitiva , Linhagem Celular , Desenho de Fármacos , Cinética , Masculino , Camundongos , Receptores do Ácido Retinoico/efeitos dos fármacos , Receptor alfa de Ácido Retinoico , Receptores X de Retinoides , Fatores de Transcrição/efeitos dos fármacos , Tretinoína/farmacocinética , Receptor gama de Ácido RetinoicoRESUMO
Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.
Assuntos
Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Caprilatos/química , Caprilatos/farmacologia , Tiazolidinedionas , Alcenos/química , Alcenos/farmacologia , Animais , Derivados de Benzeno/síntese química , Caprilatos/síntese química , Linhagem Celular , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Desenho de Fármacos , Sinergismo Farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/antagonistas & inibidores , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides , Rosiglitazona , Relação Estrutura-Atividade , Tiazóis/farmacologia , Tiroxina/sangue , Fatores de Transcrição/agonistas , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção , Triglicerídeos/sangueRESUMO
Retinoid X receptor (RXR) modulators are being evaluated as a means for the treatment of non-insulin dependent (type II) diabetes mellitus, and substantial progress has been made in the preclinical evaluation of these compounds. To aid in this process, several structural classes of RXR modulators are now under investigation. The diverse structures and syntheses of these compounds will be discussed in this review.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Receptores do Ácido Retinoico/metabolismo , Retinoides/uso terapêutico , Fatores de Transcrição/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/antagonistas & inibidores , Receptores X de Retinoides , Retinoides/química , Retinoides/metabolismo , Fatores de Transcrição/agonistas , Fatores de Transcrição/antagonistas & inibidoresRESUMO
The selective estrogen receptor modulator arzoxifene and the rexinoid LG 100268 were active not only as single agents for prevention and treatment of breast cancer in the rat model that uses nitrosomethylurea as the carcinogen but also showed striking synergy, both preventively and therapeutically, in a series of six experiments with a total of 465 rats. Mechanistic studies in cell culture reported here suggest that enhancement of stromal-epithelial interactions may contribute to this synergy. The possible clinical use of the combination of arzoxifene and LG 100268 for prevention of breast cancer in women at high risk, for treatment of women in the adjuvant setting, or for treatment of end-stage disease should now be considered.