Design, synthesis, and pharmacological evaluation of R/S-3,4-dihydro-2,2-dimethyl- 6-halo-4-(phenylaminocarbonylamino)-2H-1-benzopyrans: toward tissue-selective pancreatic beta-cell KATP channel openers structurally related to (+/-)-cromakalim.
In the search of a novel series of benzopyrans structurally related to (+/-)-cromakalim and acting as pancreatic beta-cell potassium channel openers, several R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonylamino)-2H-1-benzopyrans with or without a substituent on the phenyl ring in the 4-position were synthesized. Their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the K(ATP) channel activators (+/-)-cromakalim, diazoxide, (+/-)-pinacidil, and compound 4. Structure-activity relationships indicated that the most pronounced inhibitory activity on the pancreatic tissue was obtained by introducing a meta- or para-electron-withdrawing group (a chlorine atom) on the C-4 phenyl ring (drugs 37-42). Such molecules, unlike the parent compound (+/-)-cromakalim, also exhibited a high selectivity for the pancreatic tissue versus the vascular tissue. Radioisotopic and electrophysiological investigations performed with R/S-6-chloro-4-(3-chlorophenylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (38) confirmed that the drug activated pancreatic KATP channels.
Sebille
Sophie
S
Natural and Synthetic Drugs Research Center, Laboratoire de Chimie Pharmaceutique, Université de Liège, 1, Avenue de l'Hôpital, tour 4 (+5), Sart-Tilman, B-4000 Liège, Belgium.
Gall
David
D
de Tullio
Pascal
P
Florence
Xavier
X
Lebrun
Philippe
P
Pirotte
Bernard
B
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019806:Cromakalim / Q000737:chemistry*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C513004:6-chloro-4-(3-chlorophenylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran; D001578:Benzopyrans; D007328:Insulin; D010671:Phenylurea Compounds; D015221:Potassium Channels; D019806:Cromakalim; D000255:Adenosine Triphosphate