Synthesis and biological activity of 3,3-Diamino-sulfonylacrylonitriles as novel inhibitors of glucose induced insulin secretion from beta cells

• Published in: Bioorganic & medicinal chemistry 2003-03, Vol.11 (6), p.931-940
• Main Authors: Tagmose, Tina M, Zaragoza, Florencio, Boonen, Harrie C.M, Worsaae, Anne, Mogensen, John P, Nielsen, Flemming E, Jensen, Anette Frost, Hansen, John Bondo
• Format: Article
• Language: English
• Subjects: Acrylonitrile - analogs & derivatives; Acrylonitrile - chemical synthesis; Acrylonitrile - pharmacology; Animals; Biological and medical sciences; Crystallography, X-Ray; Diazoxide - pharmacology; Diuretics; Female; General and cellular metabolism. Vitamins; Glucose - antagonists & inhibitors; Glucose - pharmacology; Hydrogen Bonding; In Vitro Techniques; Indicators and Reagents; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Molecular Conformation; Muscle Relaxation - drug effects; Muscle, Smooth, Vascular - drug effects; Pharmacology. Drug treatments; Pinacidil - pharmacology; Rats; Rats, Wistar; Sodium Chloride Symporter Inhibitors - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(02)00534-5

Pinacidil analogues, for example, N-cyano- N′-(3,5-dichlorophenyl)- N″-(3-methylbutyl)guanidine, 1, have previously been described as potassium channel openers on beta cells and smooth muscle cells. In the present study 3,3-diamino-sulfonylacrylonitrile, a new bioisostere of the cyanoguanidine group, was investigated. 3,3-Diamino-sulfonylacrylonitriles were prepared in a two step synthesis from the corresponding isothiocyanates and sulfonylacetonitriles. Single crystal X-ray crystallography and NMR spectroscopy were used to establish the structure of 2-(4-chlorophenylsulfonyl)-3-cyclobutylamino-3-(3,5-dichlorophenylamino)acrylonitrile 3i. The analysis confirmed that 3i assumes a staggered conformation considered as the energetically most favourable. The compounds synthesised have been identified as potent inhibitors of glucose stimulated insulin secretion from beta cell lines and rat pancreatic islets with minimal effects on vascular smooth muscle. Novel 3,3-diamino-sulfonylacrylonitriles, for example 3i, have been synthesised and identified as potent inhibitors of glucose stimulated insulin secretion from beta cell lines and rat pancreatic islets with minimal effects on vascular smooth muscle.