Abstract:
:A series of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives were prepared and evaluated as inhibitors of human liver glycogen phosphorylase a (hLGPa). One compound, 5-chloro-N-[4-(1,2-dihydroxyethyl)phenyl]-1H-indole-2-carboxamide (2f), inhibited hLGPa with an IC(50) of 0.90microM. The pyridine analogue of 2f showed inhibitory activity of glucagon-induced glucose output in cultured primary hepatocytes with an IC(50) of 0.62microM and oral hypoglycemic activity in diabetic db/db mice. Crystallographic determination of the complex of 2f with hLGPa showed binding of the inhibitor in a solvent cavity at the dimer interface, with the two hydroxyl groups making favorable electrostatic interactions with hLGPa.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Onda K,Suzuki T,Shiraki R,Yonetoku Y,Negoro K,Momose K,Katayama N,Orita M,Yamaguchi T,Ohta M,Tsukamoto Sdoi
10.1016/j.bmc.2008.04.010subject
Has Abstractpub_date
2008-05-15 00:00:00pages
5452-64issue
10eissn
0968-0896issn
1464-3391pii
S0968-0896(08)00323-4journal_volume
16pub_type
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