RESUMO
We describe a practical and scalable route to compound (Z)-1, a selective CCK1 receptor antagonist. Notable features of this concise route are (1) a regioselective construction of the pyrazole core through the reaction of an aryl hydrazine and an elaborated acetylenic ketone, (2) a Tf2O/pyridine mediated Z-selective dehydration of an α-hydroxyester, and (3) a stereoselective hydrolysis. The sequence is high-yielding and amenable for large-scale synthesis.
Assuntos
Clorobenzenos/síntese química , Dioxóis/síntese química , Dioxóis/farmacologia , Hidrazinas/química , Propionatos/síntese química , Pirazóis/química , Pirazóis/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Clorobenzenos/química , Dioxóis/química , Hidrólise , Cetonas/química , Estrutura Molecular , Propionatos/química , Pirazóis/síntese química , EstereoisomerismoRESUMO
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
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
Treatment of oxazole or 5-aryl oxazoles with i-PrMgCl smoothly generates the corresponding 2-Grignard reagents, which react with Weinreb amides to provide exclusively 2-acyl oxazole products.
Assuntos
Amidas/química , Magnésio/química , Oxazóis/química , Espectroscopia de Ressonância MagnéticaRESUMO
An efficient method for the stereoselective synthesis of (Z)-alpha-arylacrylates is described. Treatment of alpha-hydroxyesters with triflic anhydride and pyridine at 0 degrees C followed by warming to room temperature afforded the corresponding (Z)-alpha-aryl-alpha,beta-unsaturated esters in very good yields and excellent stereoselectivity.
Assuntos
Ésteres/síntese química , Desidratação , Ésteres/química , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Sensibilidade e Especificidade , EstereoisomerismoRESUMO
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).