New 3-alkylamino-4H-thieno-1,2,4-thiadiazine 1,1-dioxide derivatives activate ATP-sensitive potassium channels of pancreatic beta cells

Flemming E Nielsen; Søren Ebdrup; Anette Frost Jensen; Lars Ynddal; Thora B Bodvarsdottir; Carsten Stidsen; Anne Worsaae; Harrie C M Boonen; Per O G Arkhammar; Tinna Fremming; Philip Wahl; Hanne T Kornø; J Bondo Hansen

doi:10.1021/jm060042j

New 3-alkylamino-4H-thieno-1,2,4-thiadiazine 1,1-dioxide derivatives activate ATP-sensitive potassium channels of pancreatic beta cells

J Med Chem. 2006 Jul 13;49(14):4127-39. doi: 10.1021/jm060042j.

Authors

Flemming E Nielsen¹, Søren Ebdrup, Anette Frost Jensen, Lars Ynddal, Thora B Bodvarsdottir, Carsten Stidsen, Anne Worsaae, Harrie C M Boonen, Per O G Arkhammar, Tinna Fremming, Philip Wahl, Hanne T Kornø, J Bondo Hansen

Affiliation

¹ Novo Nordisk Research and Development, Novo Nordisk Park, DK 2760 Måløv, Denmark.

PMID: 16821773
DOI: 10.1021/jm060042j

Abstract

Compound 1a (NN414) is a potent opener of Kir6.2/SUR1 K(ATP) channels. Compound 1a inhibits insulin release in vitro and in vivo and preserves beta cell function in preclinical animal models suggesting that such a compound could find use in treatment or prevention of type 1 and type 2 diabetes. The crystal structure and a convergent synthesis of 1a are presented together with a range of new analogues of 1a. Several compounds, e.g., 6-chloro-3-(1-methyl-1-phenylethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1h), were found to be potent openers of Kir6.2/SUR1 K(ATP) channels and were able to suppress glucose-stimulated insulin release from rat islets in vitro (EC(50) = 0.04 +/- 0.01 muM) and in vivo after intravenous or peroral administration to hyperinsulinemic obese Zucker rats (ED(50) = 4.0 mg/kg). Structural modifications of this series of K(ATP) channel openers have provided compounds with promising pharmacokinetic properties indicating that brief periods of beta cell rest can be achieved.

MeSH terms

Animals
Biological Availability
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Cell Line
Crystallography, X-Ray
Cyclic S-Oxides / chemical synthesis*
Cyclic S-Oxides / chemistry
Cyclic S-Oxides / pharmacology
Female
Humans
In Vitro Techniques
Insulin / blood
Ion Channel Gating
Islets of Langerhans / drug effects*
Islets of Langerhans / metabolism
Male
Membrane Potentials / drug effects
Molecular Structure
Muscle Relaxation / drug effects
Muscle, Smooth / drug effects
Muscle, Smooth / physiology
Potassium Channels, Inwardly Rectifying / chemistry
Potassium Channels, Inwardly Rectifying / drug effects*
Potassium Channels, Inwardly Rectifying / physiology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Rats, Wistar
Rats, Zucker
Structure-Activity Relationship
Thiadiazines / chemical synthesis*
Thiadiazines / chemistry
Thiadiazines / pharmacology

Substances

6-chloro-3-(1-methyl-1-phenylethyl)amino-4H-thieno(3,2-e)-1,2,4-thiadiazine
Bridged Bicyclo Compounds, Heterocyclic
Cyclic S-Oxides
Insulin
Kir6.2 channel
NN 414
Potassium Channels, Inwardly Rectifying
Thiadiazines