4-Phenylureido/thioureido-substituted 2,2-dimethylchroman analogs of cromakalim bearing a bulky 'carbamate' moiety at the 6-position as potent inhibitors of glucose-sensitive insulin secretion.
The synthesis of 2,2-dimethylchromans bearing a 3/4-chloro/cyano-substituted phenylureido or phenylthioureido moiety at the 4-position and an alkoxycarbonylamino ('carbamate') group at the 6-position is described. These new analogs of the potassium channel opener (±)-cromakalim were further tested on rat pancreatic islets as putative inhibitors of insulin release and on rat aorta rings as putative vasorelaxants. All compounds inhibited insulin secretion and induced a myorelaxant activity. Compound 14o [R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea; BPDZ 711] emerged as the most potent inhibitor of the glucose-sensitive insulin releasing process (IC50 = 0.24 μM) and displayed selectivity towards the pancreatic endocrine tissue. Radioisotopic, fluorimetric and pharmacological investigations were performed on rat pancreatic islet and rat vascular smooth muscle cells in order to decipher its mechanism of action. Our findings suggest that the mechanism of action of 14o is rather unspecific. The compound behaves as a KATP channel opener, a Ca(2+) entry blocker, and promotes an intracellular calcium translocation.
Laboratoire de Chimie Pharmaceutique, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Quartier Hôpital, Avenue Hippocrate 15, B-4000 Liège, Belgium. Electronic address: b.pirotte@ulg.ac.be.
Bernard
B
Pirotte
Laboratoire de Chimie Pharmaceutique, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Quartier Hôpital, Avenue Hippocrate 15, B-4000 Liège, Belgium; Laboratoire de Physiologie et Pharmacologie, Université Libre de Bruxelles, Faculté de Médecine, 808 Route de Lennik, B-1070 Bruxelles, Belgium.
Xavier
X
Florence
Laboratoire de Chimie Pharmaceutique, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Quartier Hôpital, Avenue Hippocrate 15, B-4000 Liège, Belgium.
Eric
E
Goffin
Laboratoire de Chimie Pharmaceutique, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Quartier Hôpital, Avenue Hippocrate 15, B-4000 Liège, Belgium.
Marlen Borges
MB
Medeiros
Laboratoire de Chimie Pharmaceutique, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, Quartier Hôpital, Avenue Hippocrate 15, B-4000 Liège, Belgium.
Pascal
P
de Tullio
Laboratoire de Physiologie et Pharmacologie, Université Libre de Bruxelles, Faculté de Médecine, 808 Route de Lennik, B-1070 Bruxelles, Belgium.
Philippe
P
Lebrun
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002219:Carbamates / Q000737:chemistry*; D019806:Cromakalim / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016257:Fura-2 / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000737:chemistry* / Q000494:pharmacology*
D002219:Carbamates; D007328:Insulin; D014665:Vasodilator Agents; D019806:Cromakalim; D005947:Glucose; D016257:Fura-2
2,2-Dimethylchromans; ATP-Sensitive potassium channels; Cromakalim analogs; Insulin secretion; Potassium channel openers; Smooth muscle contractile activity