Deciphering structure-activity relationships in a series of 2,2-dimethylchromans acting as inhibitors of insulin release and smooth muscle relaxants

5 years ago

Deciphering structure-activity relationships in a series of 2,2-dimethylchromans acting as inhibitors of insulin release and smooth muscle relaxants

Bernard Pirotte, Eric Goffin, Xavier Florence, Philippe Lebrun

4,6-Disubstituted 2,2-dimethylchromans are reported as pharmacologically active compounds mainly targeting the ATP-sensitive potassium channels (KATP channels). The present study is an attempt to characterize the impact of the nature of the substituent introduced at the 4- and 6-position 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 supposed to reflect interaction with specific ion channels. Starting from the core structure 4-amino-2,2-dimethylchroman, the progressive increase of the steric hindrance of the chemical functions 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 releasing process and, to a lesser extent, of the vasorelaxant activity. Moreover, the dextrorotatory enantiomer of one selected 2,2-dimethylchroman racemic compound (29) was more potent than its levorotatory counterpart at inhibiting the insulin secretory process. Additional pharmacological investigations suggested, however, that the myorelaxant activity of (11) and (15) resulted from a direct Ca++ entry blockade.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cmdc.201700409