title: Three-dimensional quantitative structure-activity relationships of ATP-sensitive potassium (KATP) channel openers belonging to the 3-alkylamino-4H-1,2,4-benzo- and 3-alkylamino-4H-1,2,4-pyridothiadiazine 1,1-dioxide families.
abstract: Recent studies have demonstrated that selective activation of pancreatic ATP-sensitive potassium (KATP) channels could be of clinical value in the treatment of type I and type II diabetes, obesity, and hypersinsulinemia. Taking into account these promising therapeutic opportunities, we have explored the 3-alkylamino-4H-1,2,4-pyrido- and 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide families. Among these series, numerous drugs were identified as highly potent and selective openers of either the pancreatic or the aortic KATP channels. Thanks to comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), quantitative structure-activity relationship approaches using more than 100 compounds, pharmacophoric models explaining the activity and selectivity of the drugs have been elaborated. These models highlighted the importance of several chemical regions for KATP channel activation and could be very helpful for future improvement of drug potency, selectivity, or both. Moreover, an original CoMSIA analysis, using a selectivity index (SI) as a dependent variable, was also performed with the aim of identifying the structural parameters influencing tissue selectivity.
authors.affiliation: Centre de recherche en Pharmacochimie des Substances Naturelles et Synthétiques, Laboratoire de Chimie Pharmaceutique, Université de Liège, 1 avenue de l'hôpital, B-4000 Liège, Belgium. P.deTullio@ulg.ac.be
authors.forename: Pascal
authors.initials: P
authors.lastname: de Tullio
authors.forename: Léon
authors.initials: L
authors.lastname: Dupont
authors.forename: Pierre
authors.initials: P
authors.lastname: Francotte
authors.forename: Stéphane
authors.initials: S
authors.lastname: Counerotte
authors.forename: Philippe
authors.initials: P
authors.lastname: Lebrun
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D003499:Cyclic S-Oxides / 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; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013829:Thiadiazines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D003499:Cyclic S-Oxides; D007328:Insulin; D015221:Potassium Channels; D011725:Pyridines; D013829:Thiadiazines; D000255:Adenosine Triphosphate