title: New R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-benzopyrans structurally related to (+/-)-cromakalim as tissue-selective pancreatic beta-cell K(ATP) channel openers.
abstract: The present work was aimed at exploring a series of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-benzopyrans structurally related to (+/-)-cromakalim and differently substituted at the 4- and 6-positions. The biological effects of these putative activators of ATP-sensitive potassium channels (K(ATP)) were characterized in vitro on the pancreatic endocrine tissue (inhibition of insulin release) and on the vascular smooth muscle tissue (relaxation of aorta rings). The biological activity of these new dimethylchroman derivatives was further compared to that of (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and BPDZ 73. Structure-activity relationships indicated that an improved potency for the pancreatic tissue was obtained by introducing a meta- or a para-electron-withdrawing group such as a chlorine atom on the C-4 phenyl ring, independently of the nature of the halogen atom at the 6-position of the benzopyran nucleus. Most original dimethylchroman thioureas were more potent than their 'urea' homologues and even more potent than diazoxide at inhibiting insulin release. Moreover, and unlike (+/-)-cromakalim or (+/-)-pinacidil, such compounds appeared to be highly selective towards the pancreatic tissue. Radioisotopic and fluorimetric investigations indicated that the new drugs activated pancreatic K(ATP) channels. Lastly, conformational studies suggested that the urea/thiourea dimethylchromans can be regarded as hybrid compounds between cromakalim and pinacidil.
authors.affiliation: Drug Research Center, Laboratoire de Chimie Pharmaceutique, Université de Liège, 1, Avenue de l'Hôpital, tour 4 (+5) Sart-Tilman, B-4000 Liège, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Sebille
authors.forename: Pascal
authors.initials: P
authors.lastname: de Tullio
authors.forename: Xavier
authors.initials: X
authors.lastname: Florence
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Becker
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Antoine
authors.forename: Catherine
authors.initials: C
authors.lastname: Michaux
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: Philippe
authors.initials: P
authors.lastname: Lebrun
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D019806:Cromakalim / Q000737:chemistry* / Q000494:pharmacology*; D003981:Diazoxide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D015394:Molecular Structure; D020110:Pinacidil / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011789:Quantum Theory; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013696:Temperature; D013997:Time Factors
chemical_list: C416528:7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide; D018528:ATP-Binding Cassette Transporters; D001578:Benzopyrans; D015221:Potassium Channels; D019806:Cromakalim; D020110:Pinacidil; D003981:Diazoxide