Discovery and structure-activity relationship of the first non-peptide competitive human glucagon receptor antagonists.

The first non-peptide competitive human glucagon receptor antagonist, 2-(benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethan one, NNC 92-1687 (2), is described. This antagonist has a binding affinity of 20 microM (IC50) and a functional Ki = 9.1 microM 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 microM. 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.