RESUMO
A novel enantioselective synthesis of (R)-cinacalcet with 99% enantiomeric excesses (ee) has been achieved. The main strategies of the approach include a gram-scale cobalt-catalysed asymmetric cross-coupling of racemic ester with arylzinc reagent, Hoffman-type rearrangement of acidamide, the amidation of chiral amine, and improving the ee of chiral amide from 87% to 99% via recrystallization.
RESUMO
The first cobalt-catalyzed enantioselective Negishi cross-coupling reaction, and the first arylation of α-halo esters with arylzinc halides, are disclosed. Employing a cobalt-bisoxazoline catalyst, various α-arylalkanoic esters were synthesized in excellent enantioselectivities and yields (up to 97 % ee and 98 % yield). A diverse range of functional groups, including ether, halide, thioether, silyl, amine, ester, acetal, amide, olefin and heteroaromatics is tolerated by this method. This method was suitable for gram-scale reactions, enabling the synthesis of (R)-xanthorrhizol with high enantiopurity. Radical clock experiments support the intermediacy of radicals.
RESUMO
The first two highly enantioselective palladium-catalyzed allylic alkylations with benzylic nucleophiles, activated with Cr(CO)3 , have been developed. These methods enable the enantioselective synthesis of α-2-propenyl benzyl motifs, which are important scaffolds in natural products and pharmaceuticals. A variety of cyclic and acyclic allylic carbonates are competent electrophilic partners furnishing the products in excellent enantioselectivity (up to 99 % ee and 92 % yield). This approach was employed to prepare a nonsteroidal anti-inflammatory drug analogue.
Assuntos
Paládio/química , Tolueno/química , Alquilação , CatáliseRESUMO
This article studied the possible effect of rifampicin (RIF), an inhibitor of organic anion transporting polypeptide (Oatp), on the pharmacokinetics of salvianolic acid B (SAB) in rats. Rifampicin was administered intravenously 15 min prior to SAB (5 mg/kg) in rats at doses of 0, 5.0, 10.0 and 20.0 mg/kg, respectively. The concentrations of SAB in plasma and bile were determined using a Shimadzu HPLC system coupled to a LC-MS-2010EV mass spectrometer. Compared with the control group, the AUC(0-t) and C(max) values of SAB were increased significantly, while the CL(total) and CL(bile) were decreased significantly. These results suggested that pretreatment with rifampicin prior to SAB administration could decrease significantly the total and bile elimination of SAB and alter its pharmacokinetic profiles. The influence of rifampicin on the pharmacokinetics of SAB may be attributed to the inhibition of Oatp-mediated influx.
Assuntos
Benzofuranos/farmacocinética , Bile/metabolismo , Inibidores Enzimáticos/farmacologia , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Extratos Vegetais/farmacocinética , Rifampina/farmacologia , Salvia miltiorrhiza/química , Animais , Área Sob a Curva , Benzofuranos/sangue , Benzofuranos/metabolismo , Transporte Biológico/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Interações Ervas-Drogas , Masculino , Espectrometria de Massas , Extratos Vegetais/sangue , Extratos Vegetais/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
A simple, specific, and precise liquid chromatographic-electrospray ionization mass spectrometric (LC-ESI-MS) method has been developed for determination of nimodipine concentration in human plasma. The method involves the addition of 200 microL of saturated sodium bicarbonate (NaHCO(3)) solution to plasma to improve the extraction recovery, liquid-liquid extraction of nimodipine from plasma samples with anhydrous diethyl ether, simple reversed-phase chromatography, and ESI mass spectrometric detection in negative ion selected ion monitoring mode (SIM) using target [M-] ions at m/z 417 and m/z 359 for nimodipine and nitrendipine (internal standard, IS), respectively. A complete analytical run was achieved within 3.5 min. The limit of quantification was 0.5 ng/mL. The method was validated within a linear range of 0.5-100 ng/mL. The correlation coefficient for the calibration regression line was 0.9995 or better. Intra- and inter-batch accuracy and precision were acceptable. Analyte was stable in a battery of stability studies. The method has been successfully used in a bioequivalence study.
Assuntos
Bloqueadores dos Canais de Cálcio/sangue , Cromatografia Líquida de Alta Pressão/métodos , Nimodipina/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Bloqueadores dos Canais de Cálcio/farmacocinética , Calibragem , Humanos , Limite de Detecção , Nimodipina/farmacocinética , Equivalência TerapêuticaRESUMO
BACKGROUND: Considering the chronic and repeated nature of salmon calcitonin (sCT) therapy, the oral route is a preferred route of administration. But, the oral bioavailability of sCT is very low due to enzymatic degradation and poor permeation across intestinal epithelial cells. It was the aim of this study to investigate the pharmacodynamic (PD), pharmacokinetic (PK), and mucosal injury characteristic of sCT oral delivery system. METHOD: In this study, PD experiments were performed to find a suitable releasing region of sCT, an effect absorption enhancer, and an optimal mass ratio of sCT/enhancer. In addition, the PK experiments were designed to validate the absorption enhancement of this oral delivery system. Histopathological evaluations on the intestinal mucosa were carried out to assess any potential toxicity of the absorption enhancer. RESULTS: Through the PD research, we determined that oral sCT enteric-coated capsules containing sCT and citric acid (CA) with a ratio of 1:20 may be an adaptable delivery. PK study further proved that the oral absorption of sCT was enhanced from this delivery system. Finally, no damage on intestinal mucosa was observed when rats received the delivery system containing CA for up to 7 days. CONCLUSION: These results suggested that enteric-coated capsules with a certain amount of CA might give enhanced oral delivery of peptide drugs like sCT.
Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/farmacocinética , Calcitonina/administração & dosagem , Calcitonina/farmacocinética , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/prevenção & controle , Absorção Intestinal , Animais , Conservadores da Densidade Óssea/sangue , Conservadores da Densidade Óssea/farmacologia , Calcitonina/sangue , Calcitonina/farmacologia , Cálcio/sangue , Cápsulas , Química Farmacêutica , Ácido Cítrico , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Vias de Administração de Medicamentos , Sistemas de Liberação de Medicamentos/efeitos adversos , Feminino , Mucosa Gástrica/citologia , Mucosa Gástrica/efeitos dos fármacos , Meia-Vida , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
The paper is aimed to investigate the effect of cyclosporine A (CyA) on the pharmacokinetics of ginkgolide B (GB) in rats, and to look for the mechanism of the changes in pharmacokinetic behaviors of GB. GB concentration in plasma, brain homogenate and urine samples of rats was determined by LC-MS. Effects of CyA on plasma levels, brain distributions as well as urinary excretions after intravenous administration of GB were evaluated. CyA co administrated intravenously at 10 mg kg(-1) or 20 mg kg(-1) significantly increased AUC(0-360 min) (P < 0.01) and decreased total CL of GB in rats. While co administrated CYP3A inhibitor itraconazole (ICZ) has no appreciable effect on the pharmacokinetic behavior of GB. CyA increased the brain uptake of GB in a dose-dependent manner. The brain distribution of GB was significantly increased at 5 min by different doses of CyA (P < 0.001), while at 20 and 60 min only high dose of CyA could significantly increase the levels of GB in the brain (P < 0.01 and P < 0.001). Different P-gp inhibitors CyA or verapamil (VER) or digoxin (DGX) decreased the urinary GB excretion, the urinary excretion of GB in 0-8 h were about 34.8% (P < 0.001), 59.4% (P < 0.001) and 79.7% (P < 0.05) of the control, separately. No appreciable effect of ICZ was observed on urinary excretion of GB. Coadministration of P-gp inhibitors CyA could significantly increase the plasma level, accelerate the brain distribution and decrease the urinary excretion of GB.
Assuntos
Ciclosporina/farmacologia , Ginkgolídeos/farmacocinética , Interações Ervas-Drogas , Lactonas/farmacocinética , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
A sensitive and specific liquid chromatographic-electrospray ionization mass spectrometric method was developed for quantification of salvianolic acid B in rat plasma with resveratrol as the internal standard. The analytes were separated on a reversed-phase column with acetonitrile (40%) and water (60%) containing 0.75% formic acid as mobile phase at a flow rate of 1 mL/min. Liquid-liquid extraction was adopted for the sample preparation, and the analytes were determined using electrospray negative ionization mass spectrometry in the selective monitoring mode. The method was validated over the concentration range 0.1-40 microg/mL using 0.1 mL of plasma with coefficients of correlation >0.999. The intra- and inter-day precisions of analysis were <10%, and accuracy ranged from 94 to 101%. This method was successfully applied to a pharmacokinetics of salvianolic acid B in rats.