New R/S-3,4-dihydro-2,2-dimethyl-2H-1-benzopyrans as K(ATP) channel openers: modulation of the 4-position.
The present work aimed at exploring a series of diversely 4-arylthiourea-substituted R/S-3,4-dihydro-2,2-dimethyl-6-halo-2H-1-benzopyrans structurally related to (+/-)-cromakalim. These new compounds were examined in vitro as putative potassium channel openers (PCOs) on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (relaxation of aorta ring) and their activity was compared to that of the reference K(ATP) channel activators (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and of previously reported cromakalim analogues. Structure-activity relationships indicated that the most pronounced inhibitory activity on the insulin secretory process was obtained with molecules bearing a strong meta- or para-electron-withdrawing group (CN or NO(2)) on the phenyl ring of the arylthiourea moiety at the 4-position of the benzopyran nucleus (compounds 12-23). Among those, R/S-6-chloro-4-(4-cyanophenylaminothiocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (16) was found to be the most potent benzopyran-type inhibitor of insulin release ever described. Most of these original benzopyran derivatives show increased selectivity for pancreatic versus vascular tissue. Radioisotopic investigations indicated that these new compounds activated pancreatic K(ATP) channels.
Florence
Xavier
X
Laboratoire de Chimie Pharmaceutique, Centre Interfacultaire de Recherche du Médicament (Drug Research Center), Université de Liège, C.H.U., 1 Avenue de l'Hôpital, B-4000 Liège, Belgium. xavier.florence@ulg.ac.be
Sebille
Sophie
S
Tullio
Pascal de
Pd
Lebrun
Philippe
P
Pirotte
Bernard
B
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019806:Cromakalim / Q000737:chemistry / Q000494:pharmacology; D003981:Diazoxide / Q000737:chemistry / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D020110:Pinacidil / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D001578:Benzopyrans; D015221:Potassium Channels; D014665:Vasodilator Agents; D019806:Cromakalim; D020110:Pinacidil; D000255:Adenosine Triphosphate; D003981:Diazoxide