Synthesis of 3-Amino- and 3-Substituted Amino-2H-1,2,4-benzothiadiazine 1,1-Dioxides.

Petersen, H; Mäkitie, Osmo; Smedman, Leif-Åke; Wennberg, Inger; Norbury, A. Hugh; Swahn, Carl‐Gunnar

doi:10.3891/acta.chem.scand.27-2655

Cited by 7 publications

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“…Accordingly, the diazoxide molecule has been structurally modified to improve the selectivity profile. Variations of the size of the 3-alkyl substituent, in the substitution of position 7, , and in the introduction of 3-alkylamino side chains have been reported. , By combining components from the structures of pinacidil and diazoxide, Pirotte and co-workers , have prepared a series of pyrido[4,3- e ]-1,2,4-thiadiazine 1,1-dioxides, among which BPDZ 44 ( 4 ), shown in Chart , was reported to be a more potent and selective KCO of pancreatic β-cells than diazoxide. These structures have subsequently been developed to include other potent benzo-1,2,4-thiadiazine 1,1-dioxide derivatives such as BPDZ 73 ( 5 ) .…”

Section: Introductionmentioning

confidence: 99%

Virtual Screening for Novel Openers of Pancreatic K_ATP Channels

et al. 2007

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Ligand-based virtual screening approaches were applied to search for new chemotype KCOs activating Kir6.2/SUR1 KATP channels. A total of 65 208 commercially available compounds, extracted from the ZINC archive, served as database for screening. In a first step, pharmacokinetic filtering via VolSurf reduced the initial database to 1913 compounds. Afterward, six molecules were selected as templates for similarity searches: similarity scores, obtained toward these templates, were calculated with the GRIND, FLAP, and TOPP approaches, which differently encode structural information into potential pharmacophores. In this way, we obtained 32 hit candidates, 16 via GRIND and eight each via FLAP and TOPP. For biological testing of the hit candidates, their effects on membrane potentials in HEK 293 cells expressing Kir6.2/SUR1 were studied. GRIND, FLAP, and TOPP all yielded hits, but no method top-ranked all the actives. Thus, parallel application of different approaches probably improves hit detection.

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Section: Introductionmentioning

confidence: 99%

Virtual Screening for Novel Openers of Pancreatic K_ATP Channels

et al. 2007

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“…Structural modifications of the diazoxide molecule have been described previously. These include variations of the size of the 3-alkyl substituent, in the substitution of position 7 , and in the introduction of 3-alkylamino side chains to obtain hypotensive and antiinflammatory compounds. , By combining components from the structures of pinacidil and diazoxide, Pirotte et al , have prepared a series of pyrido[4,3 -e ]-1,2,4-thiadiazine 1,1-dioxides, among which BPDZ 44 ( 4 ) (Chart ) was reported to be a more potent and selective opener of K ATP channels of pancreatic β-cells than diazoxide. These structures have subsequently been developed to include other potent benzo-1,2,4-thiadiazine 1,1 dioxide derivatives …”

Section: Introductionmentioning

confidence: 99%

6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-Dioxide Derivatives Potently and Selectively Activate ATP Sensitive Potassium Channels of Pancreatic β-Cells

et al. 2002

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6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives were synthesized and characterized as activators of adenosine 5'-triphosphate (ATP) sensitive potassium (K(ATP)) channels in the beta-cells by measuring effects on membrane potential and insulin release in vitro. The effects on vascular tissue in vitro were measured on rat aorta and small mesenteric vessels. Selected compounds were characterized as competitive inhibitors of [(3)H]glibenclamide binding to membranes of HEK293 cells expressing human SUR1/Kir6.2 and as potent inhibitors of insulin release in isolated rat islets. 6-Chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (54) was found to bind and activate the SUR1/Kir6.2 K(ATP) channels in the low nanomolar range and to be at least 1000 times more potent than the reference compound diazoxide with respect to inhibition of insulin release from rat islets. Several compounds, e.g., 3-propylamino- (30), 3-isopropylamino- (34), 3-(S)-sec-butylamino- (37), and 3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (53), which were found to be potent and beta-cell selective activators of K(ATP) channels in vitro, were found to inhibit insulin secretion in rats with minimal effects on blood pressure and to exhibit good oral pharmacokinetic properties.

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“…These include variations of the size of the 3-alkyl substituent, in the substitution of position 7 [101,102] and in introduction of 3-alkylamino side-chains to obtain hypotensive and anti-inflammatory compounds [103,104]. Through a combination of components from the structures of pinacidil and diazoxide, Pirotte et al [105] [106] have prepared a series of pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide analogs, among which BPDZ 44 and BPDZ 62 (Fig.…”

Section: Activators Of Atp Sensitive Potassium Channelsmentioning

confidence: 99%

Inhibition of Insulin Secretion as a New Drug Target in the Treatment of Metabolic Disorders

Hansen¹,

Arkhammar²,

Bödvarsdóttir³

et al. 2004

CMC

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The pattern of insulin release is crucial for regulation of glucose and lipid haemostasis. Deficient insulin release causes hyperglycemia and diabetes, whereas excessive insulin release can give rise to serious metabolic disorders, such as nesidioblastosis (Persistent Hyperinsulinemic Hypoglycemia of Infancy, PHHI) and might also be closely associated with development of type 2 diabetes and obesity. Type 2 diabetes is characterized by fasting hyperinsulinemia, insulin resistance and impaired insulin release, i.e. reduced first phase insulin release and decreased insulin pulse mass. The beta cell function of patients with type 2 diabetes slowly declines and will ultimately result in beta cell failure and increasing degrees of hyperglycemia. Type 2 diabetes, in combination with obesity and cardiovascular disorders, forms the metabolic syndrome. It has been possible to improve beta cell function and viability in preclinical models of type 1 and type 2 diabetes by reducing insulin secretion to induce beta cell rest. Clinical studies have furthermore indicated that inhibitors of insulin release will be of benefit in treatment or prevention of diabetes and obesity. Pancreatic beta cells secrete insulin in response to increased metabolism and by stimulation of different receptors. The energy status of the beta cell controls insulin release via regulation of open probability of the ATP sensitive potassium (K(ATP)) channels to affect membrane potential and the intracellular calcium concentration [Ca(2+)](i). Other membrane bound receptors and ion channels and intracellular targets that modulate [Ca(2+)](i)will affect insulin release. Thus, insulin release is regulated by e.g. somatostatin receptors, GLP-1 receptors, muscarinic receptors, cholecystokinin receptors and adrenergic receptors. Although the relationship between hyperinsulinemia and certain metabolic diseases has been known for decades, only a few inhibitors of insulin release have been characterized in vitro and in vivo. These include the K(ATP) channel openers diazoxide and NN414 and the somatostatin receptor agonist octreotide.

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Synthesis of 3-Amino- and 3-Substituted Amino-2H-1,2,4-benzothiadiazine 1,1-Dioxides.

Cited by 7 publications

References 0 publications

Virtual Screening for Novel Openers of Pancreatic K_ATP Channels

Virtual Screening for Novel Openers of Pancreatic K_ATP Channels

6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-Dioxide Derivatives Potently and Selectively Activate ATP Sensitive Potassium Channels of Pancreatic β-Cells

Inhibition of Insulin Secretion as a New Drug Target in the Treatment of Metabolic Disorders

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Synthesis of 3-Amino- and 3-Substituted Amino-2H-1,2,4-benzothiadiazine 1,1-Dioxides.

Cited by 7 publications

References 0 publications

Virtual Screening for Novel Openers of Pancreatic KATP Channels

Virtual Screening for Novel Openers of Pancreatic KATP Channels

6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-Dioxide Derivatives Potently and Selectively Activate ATP Sensitive Potassium Channels of Pancreatic β-Cells

Inhibition of Insulin Secretion as a New Drug Target in the Treatment of Metabolic Disorders

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Virtual Screening for Novel Openers of Pancreatic K_ATP Channels

Virtual Screening for Novel Openers of Pancreatic K_ATP Channels