ChemInform Abstract: EPC Syntheses and Structure-Activity Relationships of Hypoglycaemic Semicyclic Amidines.

Abstract

Abstract 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 cyclohexylmethyl-isoquinuclidone derivative which inhibited secretion at 100 μM, significantly stimulated insulin secretion 2–8-fold at 10 μM and 100 μM 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 α-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 [Ca 2+ ] i increased, probably due to Ca 2+ -entry through voltage-dependent Ca 2+ -channels. At high concentrations, where inhibition of secretion was observed, [Ca 2+ ] i still rose upon application of the amidines, indicating an additional inhibitory pathway downstream to the elevation of [Ca 2+ ] i . Even at high concentrations (100 μM), the amidines had no toxic effects on insulin secreting INS-1 cells.