[en] 4,6-Disubstituted 2,2-dimethylchromans are reported as pharmacologically active compounds that mainly target the ATP-sensitive potassium channels. The present study is an attempt to characterize the impact of the nature of substituents introduced at the 4- and 6-positions of 2,2-dimethylchromans on their capacities to inhibit insulin release from pancreatic β-cells or to relax vascular smooth muscle cells, both biological responses that are supposed to reflect interaction with specific ion channels. From the core structure 4-amino-2,2-dimethylchroman, a progressive increase in the steric hindrance of the chemical functionalities introduced at the 4-position (amino, formamido, acetamido, arylureido/thioureido) and at the 6-position (amino, formamido, acetamido, alkoxycarbonylamino) led to a progressive magnification of the inhibitory effect on the insulin release process and, to a lesser extent, of the vasorelaxant activity. Moreover, the dextrorotatory enantiomer of 2,2-dimethylchroman compound 29 was more potent than its levorotatory counterpart for inhibiting the insulin secretory process. Additional pharmacological investigations suggested, however, that the myorelaxant activity of 11 and 15 resulted from a direct Ca2+ entry blockade.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Pirotte, Bernard ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Florence, Xavier ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique ; Laboratoire de Physiologie et Pharmacologie, Université Libre de Bruxelles, Faculté de Médecine, 808 Route de Lennik, 1070, Bruxelles, Belgium
Goffin, Eric ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Lebrun, Philippe; Laboratoire de Physiologie et Pharmacologie, Université Libre de Bruxelles, Faculté de Médecine, 808 Route de Lennik, 1070, Bruxelles, Belgium
Language :
English
Title :
Deciphering Structure-Activity Relationships in a Series of 2,2-Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants.
Publication date :
2017
Journal title :
ChemMedChem
ISSN :
1860-7179
eISSN :
1860-7187
Publisher :
John Wiley and Sons Ltd, Chichester, West Sussex, Germany
This study was supported in part by grants from the National Fund for Scientific Research (F.N.R.S., Belgium) of which P.L. is a Research Director. The authors gratefully acknowledge the technical assistance of S. Counerotte, F. Leleux, and A.-M. Vanbelling-hen. The preparative chiral chromatography was performed at UCB Pharma (Braine l’Alleud, Belgium) by V. Pinilla and D. Séné-chal, and the circular dichroism experiment was realized at the Center for Protein Engineering (CIP, University of Liege, Belgium) by A. Matagne; these collaborators are gratefully acknowledged.
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