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.
Jakobsen
Palle
P
Medicinal Chemistry Research, Novo Nordisk A/S, DK-2760, Måløv, Denmark. paj@novonordisk.com
Madsen
Peter
P
Andersen
HenrikSune
H
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008956:Models, Chemical; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D051381:Rats; D013237:Stereoisomerism
D007004:Hypoglycemic Agents; D007093:Imidazoles; D007328:Insulin; D015221:Potassium Channels; D005947:Glucose