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.
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.
de Tullio
Pascal
P
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
Dupont
Léon
L
Francotte
Pierre
P
Counerotte
Stéphane
S
Lebrun
Philippe
P
Pirotte
Bernard
B
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
D003499:Cyclic S-Oxides; D007328:Insulin; D015221:Potassium Channels; D011725:Pyridines; D013829:Thiadiazines; D000255:Adenosine Triphosphate