RESUMO
A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARγ modulators (SPPARγMs) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPARγ full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARγMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARγ transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPARγ receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogues such as (5R)-5-(3-{[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl)-5-methyloxazolidinedione (51) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPARγ full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.
Assuntos
Benzimidazóis/síntese química , Dimetadiona/análogos & derivados , Hipoglicemiantes/síntese química , PPAR gama/metabolismo , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Sítios de Ligação , Células COS , Chlorocebus aethiops , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dimetadiona/síntese química , Dimetadiona/química , Dimetadiona/farmacologia , Agonismo Parcial de Drogas , Perfilação da Expressão Gênica , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Modelos Moleculares , Mutagênese , Coativadores de Receptor Nuclear/metabolismo , Oxazóis/síntese química , Oxazóis/química , Oxazóis/farmacologia , PPAR gama/agonistas , PPAR gama/genética , Pioglitazona , Conformação Proteica , Ratos , Ratos Zucker , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Ativação TranscricionalRESUMO
Two methods were developed for the synthesis of [2-11C]5,5-dimethyl-2,4-oxazolidinedione ([2-11C]DMO) for use with positron emission tomography to measure regional cerebral tissue pH in vivo in man. In both methods, A and B, [2-11C]dimethyl carbonate (DMC) was prepared from [11C]phosgene and excess of sodium methoxide in methanol containing 2-hydroxyisobutyramide (HIBA). In method A, an excess of DMC was used as a carrier, while in method B none was used. In both methods, the [2-11C]DMC solution was then heated for 10 min at 150 degrees +/- 2 degrees C causing the reaction of [2-11C]DMC with HIBA to yield [2-11C]DMO with a radiochemical purity of greater than 99%. Method A gave significantly higher radioactive yields, a pure organic product, but lower specific activities. Flash chromatography was used for the separation and purification of [2-11C]DMO prepared by method B.
Assuntos
Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Dimetadiona/síntese química , Oxazóis/síntese química , Autorradiografia , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão , Elétrons , Humanos , Indicadores e Reagentes , Marcação por Isótopo/métodos , CintilografiaRESUMO
This paper describes a fast (20 min), convenient, and high yield synthesis of "no-carrier-added" 11C-labelled 5,5-dimethyloxazoladine-2,4-dione (DMO). During the synthesis [11C]phosgene is reacted in situ with 2-hydroxy-2-methylpropionamide in the presence of KOH for 20 min in a -5 degrees C bath and then for 5 min at room temperature. Filtration through a reverse-phase (C18) Sep-Pack column purifies the final product. This synthesis yields about 40 mCi of 11C-labelled DMO (radiochemical yield 40-60%) with a chemical purity exceeding 98% and a radiochemical purity exceeding 99%. The specific activity at the end of the synthesis is 80 Ci/mmol.
Assuntos
Radioisótopos de Carbono , Dimetadiona/síntese química , Oxazóis/síntese química , Humanos , Concentração de Íons de Hidrogênio , Marcação por Isótopo/métodos , Tomografia Computadorizada de EmissãoRESUMO
No-carrier-added [2-11 C]5,5-dimethyloxazolidine-2,4-dione (DMO) has been prepared rapidly and in good radiochemical yield. The synthesis involves in situ conversion of phosgene to diethyl carbonate which reacts with 2-hydroxy-2-methylpropionamide to yield labeled DMO. HPLC purification provided up to 1.85 GBq (50 mCi) of pure [11C]-DMO for injection. The product's in vivo distribution was examined in mice and rabbits. The results are encouraging for further application to in vivo measurement of intracellular pH using positron tomography.
Assuntos
Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Dimetadiona/síntese química , Oxazóis/síntese química , Animais , Encéfalo/fisiologia , Dimetadiona/metabolismo , Concentração de Íons de Hidrogênio , Marcação por Isótopo , Camundongos , Coelhos , Distribuição Tecidual , Tomografia Computadorizada de EmissãoRESUMO
We have developed a method for the synthesis of [2-11C]5,5-dimethyl-2,4-oxazolidinedione ([2-11C]DMO) for use with positron emission tomography to measure regional tissue pH in vivo in man. [2-11C]Dimethyl carbonate (DMC) was prepared from [C-11]phosgene and excess of sodium methoxide in methanol containing dimethyl carbonate as added carrier. The [2-11C]DMC solution was then reacted with 2-hydroxyisobutyramide at 150 degrees C for 10 min to yield, after HPLC separation, [2-11C]DMO with a radiochemical yield of 20-56%. Chemical yields were 78-92%, and specific activity ranged as high as 830 mCi/millimol.
