4,6-Disubstituted 2,2-dimethylchromans structurally related to the K(ATP) channel opener cromakalim: design, synthesis, and effect on insulin release and vascular tone.
Five series (ureas, thioureas, carbamates, sulfonylureas, and amides) of 4,6-disubstituted-2,2-dimethylchromans structurally related to cromakalim were prepared and evaluated, as putative ATP-sensitive potassium channel activators, on rat pancreatic islets and rat aorta rings. The biological data indicate that most compounds were, like the reference molecule cromakalim, more active on the vascular smooth muscle tissue (myorelaxant effect on 30 mM KCl induced contractions of rat aorta rings) than on the pancreatic tissue (inhibition of 16.7 mM glucose induced insulin release from rat pancreatic islets). However, some drugs (8h, 8i, 9f, 9g, 9h, and 9i) markedly inhibited insulin release and exhibited an activity equivalent or greater than that of diazoxide. Compounds 9h and 9i were also found to be more active on pancreatic beta-cells than on vascular smooth muscle cells. Last, the amide 6b was selected in order to examine its mechanism of action on vascular smooth muscle cells. Pharmacological results suggest that the compound acted as a K(ATP) channel opener. In conclusion, the present data indicate that appropriate structural modifications can generate dimethylchromans with pharmacological profiles different from that of cromakalim.
Sebille
Sophie
S
Natural and Synthetic Drugs Research Center, Department of Medicinal Chemistry, Université de Liège, 1 av. de l'Hôpital, tour 4 (+5) Sart-Tilman, B-4000 Liège, Belgium. Sophie.Sebille@ulg.ac.be
de Tullio
Pascal
P
Becker
Bénédicte
B
Antoine
Marie-Hélène
MH
Boverie
Stéphane
S
Pirotte
Bernard
B
Lebrun
Philippe
P
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019806:Cromakalim / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D015640:Ion Channel Gating / Q000187:drug effects*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D002839:Chromans; D007328:Insulin; D015221:Potassium Channels; D014665:Vasodilator Agents; D019806:Cromakalim