RESUMO
Assessment of total vitamin D intake from foods and dietary supplements (DSs) may be incomplete if 25-hydroxyvitamin D [25(OH)D] intake is not included. However, 25(OH)D data for such intake assessments are lacking, no food or DS reference materials (RMs) are available, and comparison of laboratory performance has been needed. The primary goal of this study was to evaluate whether vitamin D3 and 25(OH)D3 concentrations in food and DS materials could be measured with acceptable reproducibility. Five experienced laboratories from the United States and other countries participated, all using liquid chromatography tandem-mass spectrometry but no common analytical protocol; however, various methods were used for determining vitamin D3 in the DS. Five animal-based materials (including three commercially available RMs) and one DS were analyzed. Reproducibility results for the materials were acceptable. Thus, it is possible to obtain consistent results among experienced laboratories for vitamin D3 and 25(OH)D3 in foods and a DS.
Assuntos
Cromatografia Líquida/métodos , Suplementos Nutricionais/análise , Análise de Alimentos , Espectrometria de Massas em Tandem/métodos , Vitamina D/análogos & derivados , Vitamina D/análiseRESUMO
A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new class of sirtuin inhibitors with a preference for SIRT1 over SIRT2.
Assuntos
Compostos Bicíclicos com Pontes/química , Pirazóis/química , Sirtuína 1/antagonistas & inibidores , Sirtuína 2/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Simulação de Dinâmica Molecular , Ligação Proteica , Pirazóis/síntese química , Pirazóis/metabolismo , Sirtuína 1/metabolismo , Sirtuína 2/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor.
Assuntos
Anti-Hipertensivos/química , Piperidinas/química , Inibidores de Proteases/química , Renina/antagonistas & inibidores , Compostos de Espiro/química , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Cães , Desenho de Fármacos , Humanos , Hipertensão/tratamento farmacológico , Macaca mulatta , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Ratos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
An efficient and convenient methodology for the synthesis of the 3-(trans-2-aminocyclopropyl) alanine and 3-(trans-2-nitrocyclopropyl) alanine moieties found in the core of belactosin A and hormaomycin, respectively, is reported. By using an enantioenriched substituted alpha-nitro diazoester in a diastereoselective intramolecular cyclopropanation reaction, the trans-nitrocyclopropyl alanine moiety can be obtained efficiently in five steps from the initial alpha-nitrocyclopropyl lactone unit, thus achieving the synthesis of the cyclopropane core of the two natural products.
Assuntos
Alanina/análogos & derivados , Alanina/síntese química , Produtos Biológicos/síntese química , Ciclopropanos/química , Depsipeptídeos/síntese química , Peptídeos/síntese química , Alanina/química , Alanina/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Catálise , Ciclização , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular , Estrutura Molecular , Peptídeos/química , Peptídeos/farmacologia , EstereoisomerismoRESUMO
We have identified the N(1)-benzyl-N(2)-methylethane-1,2-diamine unit as a substitute for the (S)-alanine benzylamide moiety for the design of co-activator associated arginine methyltransferase 1 (CARM1) inhibitors. The potency of these inhibitors is in the same order of magnitude as their predecessors and their clearance, volume of distribution, and half lives were greatly improved.
Assuntos
Diaminas/farmacologia , Inibidores Enzimáticos/farmacologia , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Diaminas/síntese química , Diaminas/química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.