benzofurans and propionic-acid

Fu-Ke-Zai-Zao pills, the famous traditional Chinese medicine formula, composed of 42 medicinal herbs, have been widely used to treat various gynecological diseases. However, the chemical constituents and metabolic profiling of Fu-Ke-Zai-Zao pills remain largely unknown, which hampers improvement of the quality control and pharmacological elucidation of this formula. In the present study, a sensitive and selective ultra high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry method was developed to separate and identify the comprehensive chemical constituents of Fu-Ke-Zai-Zao pills. According to the results, a total of 83 compounds were identified, including phenylpropionic acids, flavonoids, terpenoids, triterpene saponins, and phthalides, and 81 compounds were first reported in Fu-Ke-Zai-Zao pills. Moreover, the absorbed components and metabolites in rat plasma after intragastric administration of Fu-Ke-Zai-Zao pills were also detected by the same analytical method. A total of 36 compounds were identified, including 21 prototypes and 15 metabolites. The latter were generated through the metabolic pathways of methylation and glucuronidation, and glucuronidated metabolites were the main constituents in the plasma. This is the first systematic study on the chemical constituents and metabolic profiling of Fu-Ke-Zai-Zao pills, and the results provide valuable chemical information for further elucidating pharmacological effects and mechanism of action of Fu-Ke-Zai-Zao pills.

Topics: Animals; Benzofurans; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Female; Flavonoids; Methylation; Monoterpenes; Plasma; Propionates; Quality Control; Rats; Rats, Sprague-Dawley; Saponins; Tandem Mass Spectrometry; Triterpenes

The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT). Further optimization gave rise to the benzofuran propanoic acid series (exemplified by compound 37), which demonstrated acute mechanism-based pharmacodynamic effects. The combination of in vivo efficacy and attractive rodent pharmacodynamic profiles suggests compounds generated from this series may afford attractive candidates for the treatment of Type 2 diabetes.

Topics: Animals; Benzofurans; Blood Glucose; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Humans; Hypoglycemic Agents; Mice; Propionates; Receptors, G-Protein-Coupled

The new fluorescent Na+ indicator sodium-binding benzofuran isophthalate (SBFI) was used for determination of the cytosolic free Na+ concentration, [Na+]i, in human platelets. The dye could be loaded into platelets in the form of its acetoxymethyl ester (SBFI-AM). Calibration of the fluorescence in terms of [Na+]i was done by measuring the 345/385 nm excitation ratio (emission 490 nm) at various extracellular Na+ concentrations, [Na+]o, in the presence of gramicidin D. The 345/385 intensity ratio increased almost linearly when [Na+]i was stepwise raised from 20 to 60 mM. The basal value for [Na+]i was found to be 26.0 +/- 4.5 mM (n = 15). Incubation of platelets in Na(+)-free buffer decreased [Na+]i, whereas inhibition of the (Na+ + K+)-ATPase by 0.5 mM ouabain increased [Na+]i to 56 +/- 4 mM (n = 4) within 60 min. Activation of Na+/H+ exchange by exposing platelets to propionic acid also raised [Na+]i, and a comparable effect was produced by the Na+/H+ ionophore monensin. Activation of platelets with thrombin (0.1-0.5 unit/ml) also increased the 345/385 nm intensity ratio, an effect that was not seen in Na(+)-free buffer or after raising intracellular cAMP by treatment of platelets with prostaglandin E1. On the average, [Na+]i was raised to 59.5 +/- 5.3 mM (n = 15) at 10 min after addition of thrombin without a significant decrease for further 10 min. An increase in [Na+]i was also seen when platelets were challenged with the Ca2+ ionophore ionomycin, an effect that did not occur in the absence of Na+o. Our findings confirm earlier reports which demonstrated a rise in [Na+]i in stimulated platelets and show that SBFI is a useful tool for determination of [Na+]i in resting and stimulated platelets.

Topics: Alprostadil; Benzofurans; Blood Platelets; Carrier Proteins; Cyclic AMP; Cytosol; Ethers, Cyclic; Fluorescent Dyes; Humans; Ionomycin; Monensin; Ouabain; Platelet Activation; Propionates; Sodium; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase; Spectrometry, Fluorescence; Thrombin