Discovery of N-Aryl-2-acylindole human glucagon receptor antagonists
ABSTRACT A novel class of N-aryl-2-acylindole human glucagon receptor (hGCGR) antagonists is reported. These compounds demonstrate good pharmacokinetic profiles in multiple preclinical species. One compound from this series, indole 33, is orally active in a transgenic murine pharmacodynamic model. Furthermore, a 1mg/kg oral dose of indole 33 lowers ambient glucose levels in an ob/ob/hGCGR transgenic murine diabetes model. This compound was deemed suitable for preclinical safety studies and was found to be well tolerated in an 8-day experimental rodent tolerability study. The combination of preclinical efficacy and safety observed with compound 33 highlights the potential of this class as a treatment for type 2 diabetes.
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ABSTRACT: Cinnamomum burmannii Blume (cinnamon stick) from Indonesia is a little-investigated spice. In this study, the antibacterial activity, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) of cinnamon stick extract were evaluated against five common foodborne pathogenic bacteria (Bacillus cereus, Listeria monocytogenes, Staphylococcus aureus, Escherichia coli, and Salmonella anatum). Cinnamon stick extract exhibited significant antibacterial properties. Major compounds in cinnamon stick were tentatively identified by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography (LC-MS) as a predominant volatile oil component ((E)-cinnamaldehyde) and several polyphenols (mainly proanthocyanidins and (epi)catechins). Both (E)-cinnamaldehyde and proanthocyanidins significantly contributed to the antibacterial properties. Additionally, scanning electron microscopy was used to observe morphological changes of bacteria treated with the crude extract of cinnamon stick and its major components. This study suggests that cinnamon stick and its bioactive components have potential for application as natural food preservatives.Journal of Agricultural and Food Chemistry 08/2007; 55(14):5484-90. DOI:10.1021/jf070424d · 2.91 Impact Factor
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ABSTRACT: The natural antimicrobial compound carvacrol was investigated for its effect on diarrheal toxin production by Bacillus cereus. Carvacrol (0-0.06 mg/ml) reduced the viable count and the maximal specific growth rate (mumax) of B. cereus in BHI broth. The total amount of protein was not affected by carvacrol. However, a sharp decrease (80%) in diarrheal toxin production was observed in the presence of 0.06 mg/ml carvacrol. Carvacrol also inhibited toxin production in soup, but approximately 50-fold higher concentrations were needed to achieve the same effect as in broth. From this study it can be concluded that carvacrol can be added to food products at doses below the MIC value, thereby reducing the risk of toxin production by B. cereus and increasing the safety of the products.International Journal of Food Microbiology 04/2001; 64(3):373-8. DOI:10.1016/S0168-1605(00)00480-3 · 3.08 Impact Factor
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ABSTRACT: A mixture of Carica papaya latex (0.41 mg protein ml-1) and fluconazole (2 micrograms ml-1) showed a synergistic action on the inhibition of Candida albicans growth. Thus, with this mixture an equivalent inhibition rate was observed to that obtained when C. albicans was cultured in a medium supplemented with a two-fold concentration (4 micrograms ml-1) of fluconazole alone. This synergistic effect resulted in partial cell wall degradation as indicated by transmission electron microscopy observations. An increase of fluconazole concentration from 2 micrograms ml-1 to 4 micrograms ml-1 involved a small decrease of MIC 80% from latex (150 to 130 micrograms protein ml-1). Measure of MIC 80% from fluconazole mixed with latex in a subinhibitory concentration (85 micrograms protein ml-1) allows the determination of an effective fluconazole concentration (4 micrograms ml-1) inferior to mean plasmatic dose observed in human therapy. The potential therapeutic use of latex in combination with a synthetic antifungal is discussed.Mycoses 01/1998; 40(11-12):429-37. DOI:10.1111/j.1439-0507.1997.tb00180.x · 2.24 Impact Factor