RESUMO
Gonadotropin-releasing hormone (GnRH) receptor antagonists are an important class of compounds designed to block the pituitary gland from synthesizing follicle-stimulating hormone and luteinizing hormone for the treatment of sex hormone dependent disorders. Elagolix (ABT-620) is currently approved for the treatment of pain associated with endometriosis and as a combination with estradiol and norethindrone acetate is approved for management of heavy menstrual bleeding due to uterine fibroids. In order to support the development of elagolix, we prepared [3 H]elagolix for preclinical metabolism studies and [14 C]elagolix for environmental risk assessment studies.
Assuntos
LeiomiomaRESUMO
The greatest challenge standing in the way of effective in vivo siRNA delivery is creating a delivery vehicle that mediates a high degree of efficacy with a broad therapeutic window. Key structure-activity relationships of a poly(amide) polymer conjugate siRNA delivery platform were explored to discover the optimized polymer parameters that yield the highest activity of mRNA knockdown in the liver. At the same time, the poly(amide) backbone of the polymers allowed for the metabolism and clearance of the polymer from the body very quickly, which was established using radiolabeled polymers to demonstrate the time course of biodistribution and excretion from the body. The fast degradation and clearance of the polymers provided for very low toxicity at efficacious doses, and the therapeutic window of this poly(amide)-based siRNA delivery platform was shown to be much broader than a comparable polymer platform. The results of this work illustrate that the poly(amide) platform has a promising future in the development of a siRNA-based drug approved for human use.
Assuntos
Materiais Biocompatíveis/síntese química , Portadores de Fármacos/síntese química , Fígado/metabolismo , Nylons/síntese química , Peptídeos/síntese química , RNA Interferente Pequeno/administração & dosagem , Animais , Autorradiografia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Materiais Biocompatíveis/toxicidade , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Desenho de Fármacos , Estabilidade de Medicamentos , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Fígado/diagnóstico por imagem , Macaca mulatta , Nylons/química , Nylons/farmacocinética , Nylons/toxicidade , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/toxicidade , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/toxicidade , Cintilografia , Ratos Sprague-Dawley , Especificidade da Espécie , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Cholesteryl ester transfer protein inhibitors are an important class of compounds designed to treat hypocholesterolemia and prevent cardiovascular disease. Anacetrapib (MK-0859) is currently in phase III trials for the treatment of elevated cholesterol levels and prevention of cardiovascular disease. In order to further support the development of anacetrapib, we prepared [M + 6]MK-0859, which was required in support of an absolute bioavailability study of the active pharmaceutical ingredient (API). Additional support included the synthesis of an internal standard [M + 13] and three stable isotope labeled metabolites, which were used to analyze clinical samples, and [(14) C]MK-0859 to support drug metabolism studies.
Assuntos
Anticolesterolemiantes/síntese química , Oxazolidinonas/síntese química , Compostos Radiofarmacêuticos/síntese química , Radioisótopos de Carbono/química , Marcação por IsótopoRESUMO
The disposition of vorinostat, an anticancer agent, was investigated in rats and dogs. Vorinostat possessed high serum clearance, a short elimination half-life and low oral bioavailability in both species. The renal route played an important role in the elimination of drug-related material and vorinostat was eliminated primarily by metabolic biotransformation.
Assuntos
Antineoplásicos/farmacocinética , Inibidores Enzimáticos/farmacocinética , Ácidos Hidroxâmicos/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Inibidores de Histona Desacetilases , Masculino , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Distribuição Tecidual , VorinostatRESUMO
To support pharmacokinetic studies, a selective and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simultaneous determination of a novel KDR kinase inhibitor (1) and its active metabolite (2) in human plasma. The method is fully automated using a Packard MultiPROBE II system and a TomTec Quadra 96 liquid handling workstation to perform sample preparation and solid-phase extraction (SPE). Following the extraction on a mixed-mode SPE using Oasis MCX 96-well plate, the analytes were separated on a Aquasil C18 column (50 mm x 2.1 mm, i.d., 3 microm) with a mobile phase consisting of acetonitrile/ammonium acetate buffer (5 mM, pH 5.0) (60/40, v/v). The run time for each injection was 4.5 min with the retention times of approximately 2.0 and 2.7 min for 1 and 2 respectively, at a flow rate of 0.25 mL/min. A tandem mass spectrometric detection was conducted using multiple reaction monitoring (MRM) under the positive ion mode with a turbo ion-spray interface. The linear ranges of the calibration curves were 0.05-400 ng/mL for 1 and 0.1-400 ng/mL for 2 on a PE Sciex API 4000 LC-MS/MS system. The lower limits of quantitation (LLOQ) of the assay were 0.05 and 0.1 ng/mL for 1 and 2 respectively, when 0.4 mL of plasma was processed. Intra-day assay precision (using five standard curves prepared by spiking compounds to five lots of plasma) was less than 4.9% for 1 and less than 9.6% for 2 on each concentration. Assay accuracy was found to be 95.1-104.6% of nominal for 1 standards and 93.5-105.6% for 2 standards. QC samples were stable when kept at room temperature for 4 h, at -70 degrees C for 10 days, and after three freeze-thaw cycles. The extraction recoveries were 80%, 83% and 84% for 1 and 2 and I.S. respectively, and no significant matrix effects were observed. The method was successfully applied to plasma samples from clinical studies after oral administration of compound 1.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Espectrometria de Massas/métodos , Óxidos/metabolismo , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Hypervalent azido- and cyanosilicate derivatives, prepared in situ by the reaction of trimethylsilyl azide or trimethylsilyl cyanide, respectively, with tetrabutylammonium fluoride, are effective sources of nucleophilic azide or cyanide. Primary and secondary alkyl halides and sulfonates undergo rapid and efficient azide or cyanide displacement in the absence of phase transfer catalysts with the silicate derivatives. Application of these reagents to the stereoselective synthesis of glycosyl azide derivatives is reported.