کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1360954 | 981453 | 2008 | 12 صفحه PDF | دانلود رایگان |
As a result of the various N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives with a hydroxy moiety synthesized in an effort to discover novel glycogen phosphorylase (GP) inhibitors, 5-chloro-N-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (5b) was found to have potent inhibitory activity. The introduction of fluorine atoms both at a position adjacent to the hydroxy group and in the central benzene moiety lead to the optically active derivative 5-chloro-N-[(5R)-1,3,6,6-tetrafluoro-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1H-indole-2-carboxamide (25eα, which was the most potent compound in this series (IC50 = 0.020 μM). This compound inhibited glucagon-induced glucose output in cultured primary hepatocytes with an IC50 value of 0.69 μM, and showed oral hypoglycemic activity in diabetic db/db mice at 10 mg/kg. Compound 25eα also had an excellent pharmacokinetic profile, with high oral bioavailability and a long plasma half-life, in male SD rats. The binding mode of 25eα to this molecule and the role of fluorine atoms in that binding were speculated in an enzyme docking study.
5-Chloro-N-[(5R)-1,3,6,6-tetrafluoro-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1H-indole-2-carboxamide are potent inhibitors of human liver glycogen phosphorylase a (hLGPa) that inhibited glucagon-induced glucose output in cultured primary hepatocytes and showed oral hypoglycemic activity in diabetic db/db mice.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 16, Issue 23, 1 December 2008, Pages 10001–10012