title: Hydroxylated analogues of ATP-sensitive potassium channel openers belonging to the group of 6- and/or 7-substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides: toward an improvement in sulfonylurea receptor 1 selectivity and metabolism stability.
abstract: Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a.
authors.affiliation: Drug Research Center, Laboratoire de Chimie Pharmaceutique, Université de Liège, Centre Hospitalier Universitaire de Liège, 1 Avenue de l'Hôpital, B36, 4000 Liège, Belgium. p.detullio@ulg.ac.be
authors.forename: Pascal
authors.initials: P
authors.lastname: de Tullio
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Servais
authors.forename: Marianne
authors.initials: M
authors.lastname: Fillet
authors.forename: Florian
authors.initials: F
authors.lastname: Gillotin
authors.forename: Fabian
authors.initials: F
authors.lastname: Somers
authors.forename: Patrice
authors.initials: P
authors.lastname: Chiap
authors.forename: Philippe
authors.initials: P
authors.lastname: Lebrun
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D015640:Ion Channel Gating; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009928:Organ Specificity; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D051381:Rats; D011955:Receptors, Drug / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D064233:Sulfonylurea Receptors; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D013829:Thiadiazines; D014665:Vasodilator Agents; D000099161:Kcnj11 Channel; C570534:7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide; C577509:Abcc8 protein, rat