Deciphering Structure–Activity Relationships in a Series of 2,2‐Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants

• Published in: ChemMedChem Vol. 12; no. 21; pp. 1810 - 1817
• Main Authors: Pirotte, Bernard, Florence, Xavier, Goffin, Eric, Lebrun, Philippe
• Format: Journal Article Web Resource
• Language: English
• Published: Germany Wiley Subscription Services, Inc 08-11-2017; John Wiley and Sons Ltd
• Subjects: Animals; Aorta; Aorta - drug effects; Aorta - physiology; Beta cells; Biochemistry; Calcium; Calcium influx; Cells, Cultured; chromans; Chromans - chemistry; Chromans - pharmacology; Drug Discovery; General Pharmacology, Toxicology and Pharmaceutics; Human health sciences; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Ion channels; medicinal chemistry; Molecular Medicine; Muscle relaxants; Muscle, Smooth, Vascular; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Neuromuscular Agents; Neuromuscular Agents - chemistry; Neuromuscular Agents - pharmacology; Organic Chemistry; Pancreas; Pharmacie, pharmacologie & toxicologie; Pharmacology; Pharmacology, Toxicology and Pharmaceutics (all); Pharmacy, pharmacology & toxicology; Potassium; Potassium channels; Rats; Rats, Wistar; Sciences de la santé humaine; Smooth muscle; Steric hindrance; Structure-Activity Relationship; Structure-activity relationships; substituent effects; structure-activity relationships; substituent effects; ion channels; medicinal chemistry; chromans
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.201700409

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.
The impact of various substituents at the 4‐ and 6‐positions of 2,2‐dimethylchromans on the capacity to inhibit insulin release or relax smooth muscle cells was characterized. An increase in steric hindrance led to increased inhibitory activity on insulin release (in the order 9<11≈15≪<8) and, to a lesser extent, of the myorelaxant activity on vascular smooth muscle (in the order 9≪11≈15≈8).