Discovery and Structure−Activity Relationship of the First Non-Peptide Competitive Human Glucagon Receptor Antagonists

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Abstract
The first non-peptide competitive human glucagon receptor antagonist, 2-(benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethanone, NNC 92-1687 (2), is described. This antagonist has a binding affinity of 20 μM (IC50) 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.