219917-58-5Relevant academic research and scientific papers
Discovery and structure-activity relationship of the first non-pep tide competitive human glucagon receptor antagonists
Madsen, Peter,Knudsen, Lotte B.,Wiberg, Finn C.,Carr, Richard D.
, p. 5150 - 5157 (2007/10/03)
The first non-peptide competitive human glucagon receptor antagonist, 2-(benzimidazol-2ylthio)-l-(3,4-dihydroxyphenyl)-l-ethanone, NNC 92-1687 (2), is described. This antagonist has a binding affinity of 20 μM (ICso) and a functional Ki = 9.1 μM at the human glucagon receptor. A structure-activity relationship (SAR) was obtained on this compound, and the results show that only the benzimidazole part can be changed without complete loss of affinity. Analogues with tert-butyl or benzyloxy groups in the 5-position of the benzimidazole moiety were found to be equipotent or slightly more potent, all displaying binding affinities around 5-20 μM. Most of the changes to the catechol and the linker gave compounds without any affinity toward the human glucagon receptor. The 3-hydroxy group could, however, in the presence of a 4-hydroxy group be changed to a methoxy or a chloro group while retaining affinity.
