EPC syntheses and structure-activity relationships of hypoglycaemic semicyclic amidines

A series of homochiral sterically hindered mono- and bicyclic amidines was prepared as hypoglycaemic agents by lethargic reaction of O-methylcaprolactim and 3-ethoxy-2-azabicyclo[2.2.2]oct-2-ene, respectively, with homochiral cis-2-substituted cyclopentane amines provided by asymmetrical reductive amination of racemic 2-substituted cyclopentanones. All compounds, except the cyclohexylmethylisoqoinuclidone derivative which inhibited secretion at 100 mu M, significantly stimulated insulin secretion 2-8-fold at 10 mu M and 100 mu M in INS-1 cells. The most potent activator was the 2-cyclopentyl-substituted caprolactam derivative 5e. The stimulatory effects on secretion increased with rising steric hindrance of both the amidine alpha-carbon and the bicyclic amidine moiety itself. Enantiomeric discrimination was observed for the 2-[(cis-2-bulkysubstituted cyclopentyl)imino]hexahydroazepine halides 5e and 5f and for the 3-[(cis-2-substituted cyclopentyl)imino]-2-azabicyclo[2.2.2]octane halides 6a and 6c. The amidines depolarized INS-1 cells and generated action potentials, accompanied by a decrease of membrane conductance. Simultaneously [Ca2+](i) increased, probably due to Ca2+-entry through voltage-dependent Ca2+-channels. At high concentrations, where inhibition of secretion was observed, [Ca2+](i) still rose upon application of the amidines, indicating an additional inhibitory pathway downstream to the elevation of [Ca2+](i). Even at high concentrations (100 mu M), the amidines had no toxic effects on insulin secreting INS-1 cells. (C) 2000 Editions scientifiques et medicales Elsevier SAS.