Imidazolines as efficacious glucose-dependent stimulators of insulin secretion

Synthesis of a series of imidazolines with glucose dependent effects on insulin exocytosis from pancreatic beta-cells is reported. Regioisomers and enantiomers were found to exhibit marked differences in exocytotic effects as well as different activities on the K(ATP)-channel; the (R (+)) isomer of 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-thiophene-2-ylethyl]pyridine (4a) and the (+) isomer of 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-thiophene-3-ylethyl]pyridine (4d) were found to give a significant increase in insulin release-in contrast to findings for their enantiomers-without influence on the K(ATP)-channel. The (+) isomer (4a) showed glucose dependent insulin release from beta-cells at concentrations above 2.5 mM and a marked glucose lowering effect in ob/ob mice as well as in fed but not in fasted rats.