Synthesis and biological activity of 3,3-diamino-sulfonylacrylonitriles as novel inhibitors of glucose induced insulin secretion from beta cells.
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.
Tagmose
Tina M
TM
Health Care Discovery and Development Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark.
Zaragoza
Florencio
F
Boonen
Harrie C M
HC
Worsaae
Anne
A
Mogensen
John P
JP
Nielsen
Flemming E
FE
Jensen
Anette Frost
AF
Hansen
John Bondo
JB
D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D018360:Crystallography, X-Ray; D003981:Diazoxide / Q000494:pharmacology; D004232:Diuretics; D005260:Female; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D020110:Pinacidil / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology
D004232:Diuretics; D007202:Indicators and Reagents; D007328:Insulin; D049993:Sodium Chloride Symporter Inhibitors; D020110:Pinacidil; D005947:Glucose; D000181:Acrylonitrile; D003981:Diazoxide