DrugBank: Diazoxide (DB01119)

targets (6)

Identification

Name

Diazoxide

Accession Number

DB01119 (APRD00914)

Type

small molecule

Groups

approved

Description

A benzothiadiazine derivative that is a peripheral vasodilator used for hypertensive emergencies. It lacks diuretic effect, apparently because it lacks a sulfonamide group. [PubChem]

Structure

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

Not Available

Brand names

Dizoxide
Eudemine
Hyperstat
Hypertonalum
Mutabase
Proglicem
Proglycem

Brand name mixtures

Not Available

Categories

Antihypertensive Agents
Vasodilator Agents
Diuretics, Thiazide

CAS number

364-98-7

Weight

Average: 230.671
Monoisotopic: 229.991675875

Chemical Formula

C₈H₇ClN₂O₂S

InChI Key

InChIKey=GDLBFKVLRPITMI-UHFFFAOYSA-N

InChI

InChI=1S/C8H7ClN2O2S/c1-5-10-7-3-2-6(9)4-8(7)14(12,13)11-5/h2-4H,1H3,(H,10,11)

Plain Text

IUPAC Name

7-chloro-3-methyl-4H-1$l^{6},2,4-benzothiadiazine-1,1-dione

SMILES

CC1=NS(=O)(=O)C2=C(N1)C=CC(Cl)=C2

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Benzenesulfonamides

Substructures

Sulfonyls
Benzene and Derivatives
Aryl Halides
Benzenesulfonamides
Halobenzenes
Heterocyclic compounds
Aromatic compounds
Carboxamidines
Thiadiazines
Sulfonamides
Imines
Anilines

Pharmacology

Indication

Used parentally to treat hypertensive emergencies. Also used to treat hypoglycemia secondary to insulinoma.

Pharmacodynamics

Diazoxide is a potassium channel activator, which causes local relaxation in smooth muscle by increasing membrane permeability to potassium ions. This switches off voltage-gated calcium ion channels which inhibits the generation of an action potential.

Mechanism of action

As a diuretic, diazoxide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like diazoxide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of diazoxide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle. As a antihypoglycemic, diazoxide inhibits insulin release from the pancreas, probably by opening potassium channels in the beta cell membrane.

Absorption

Readily absorbed following oral administration.

Volume of distribution

Not Available

Protein binding

Very high (more than 90%) to serum proteins.

Metabolism

Hepatic.

Route of elimination

Proglycem is extensively bound (more than 90%) to serum proteins, and is excreted in the kidneys.

Half life

28 ±8.3 hours in normal adults.

Clearance

Not Available

Toxicity

Oral LD₅₀ in rat and mouse: 980 mg/kg and 444 mg/kg, respectively.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Teva branded pharmaceutical products r&d inc
Abraxis pharmaceutical products
Schering corp sub schering plough corp
Teva global respiratory research llc

Packagers

Dosage forms

Form	Route	Strength
Capsule	Oral

Prices

Unit description	Cost	Unit
Proglycem 50 mg/ml Suspension 30ml Bottle	197.05 USD	bottle
Diazoxide powder	85.07 USD	g
Proglycem 100 mg Capsule	1.65 USD	capsule

Patents

Not Available

Properties

State

solid

Melting point

330.5 oC

Experimental Properties

Property	Value	Source
water solubility	2850 mg/L	PhysProp
logP	1.3	PhysProp
pKa	8.74	Various sources

Predicted Properties

Property	Value	Source
water solubility	5.52e-01 g/l	ALOGPS
logP	1.09	ALOGPS
logP	1.00	ChemAxon Molconvert
logS	-2.62	ALOGPS
pKa		ChemAxon Molconvert
hydrogen acceptor count	4	ChemAxon Molconvert
hydrogen donor count	1	ChemAxon Molconvert
polar surface area	58.53	ChemAxon Molconvert
rotatable bond count	0	ChemAxon Molconvert
refractivity	54.84	ChemAxon Molconvert
polarizability	20.98	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Not Available

External Links

Resource	Link
KEGG Drug	D00294
KEGG Compound	C06949
PubChem Compound	3019
PubChem Substance	46508027
ChemSpider	2911
ChEBI	4495
ChEMBL	4495
Therapeutic Targets Database	DAP000956
PharmGKB	PA449285
Drug Product Database	503347
Drugs.com	http://www.drugs.com/cdi/diazoxide-suspension.html
Wikipedia	http://en.wikipedia.org/wiki/Diazoxide

ATC Codes

C02DA01
V03AH01

AHFS Codes

24:08.20

PDB Entries

Not Available

FDA label

Not Available

MSDS

show (73 KB)

Interactions

Drug Interactions

Not Available

Food Interactions

Not Available

Targets
1. ATP-sensitive inward rectifier potassium channel 11 Pharmacological action: yes Actions: inducer This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium Organism class: human UniProt ID: Q14654 Gene: KCNJ11 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: D’hahan N, Moreau C, Prost AL, Jacquet H, Alekseev AE, Terzic A, Vivaudou M: Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12162-7. Pubmed Sakura H, Trapp S, Liss B, Ashcroft FM: Altered functional properties of KATP channel conferred by a novel splice variant of SUR1. J Physiol. 1999 Dec 1;521 Pt 2:337-50. Pubmed Shindo T, Katayama Y, Horio Y, Kurachi Y: MCC-134, a novel vascular relaxing agent, is an inverse agonist for the pancreatic-type ATP-sensitive K(+) channel. J Pharmacol Exp Ther. 2000 Jan;292(1):131-5. Pubmed de Lonlay P, Fournet JC, Touati G, Groos MS, Martin D, Sevin C, Delagne V, Mayaud C, Chigot V, Sempoux C, Brusset MC, Laborde K, Bellane-Chantelot C, Vassault A, Rahier J, Junien C, Brunelle F, Nihoul-Fekete C, Saudubray JM, Robert JJ: Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases. Eur J Pediatr. 2002 Jan;161(1):37-48. Pubmed Russ U, Lange U, Loffler-Walz C, Hambrock A, Quast U: Binding and effect of K ATP channel openers in the absence of Mg2+. Br J Pharmacol. 2003 May;139(2):368-80. Pubmed 2. Carbonic anhydrase 1 Pharmacological action: yes Actions: inhibitor Reversible hydration of carbon dioxide Organism class: human UniProt ID: P00915 Gene: CA1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Domoki F, Bari F, Nagy K, Busija DW, Siklos L: Diazoxide prevents mitochondrial swelling and Ca2+ accumulation in CA1 pyramidal cells after cerebral ischemia in newborn pigs. Brain Res. 2004 Sep 3;1019(1-2):97-104. Pubmed Erdemli G, Krnjevic K: Diazoxide suppresses slowly-inactivating outward and inward currents in CA1 hippocampal neurones. Neuroreport. 1993 Dec 13;5(3):249-51. Pubmed Erdemli G, Krnjevic K: Actions of diazoxide on CA1 neurons in hippocampal slices from rats. Can J Physiol Pharmacol. 1995 May;73(5):608-18. Pubmed Scuvee-Moreau J, Seutin V, Vrijens B, Pirotte B, De Tullio P, Massotte L, Albert A, Delarge J, Dresse A: Effect of potassium channel openers on the firing rate of hippocampal pyramidal cells and A10 dopaminergic neurons in vitro. Arch Physiol Biochem. 1997 Sep;105(5):421-8. Pubmed Crepel V, Rovira C, Ben-Ari Y: The K+ channel opener diazoxide enhances glutamatergic currents and reduces GABAergic currents in hippocampal neurons. J Neurophysiol. 1993 Feb;69(2):494-503. Pubmed 3. Carbonic anhydrase 2 Pharmacological action: yes Actions: inhibitor Reversible hydration of carbon dioxide Organism class: human UniProt ID: P00918 Gene: CA2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Munoz A, Nakazaki M, Goodman JC, Barrios R, Onetti CG, Bryan J, Aguilar-Bryan L: Ischemic preconditioning in the hippocampus of a knockout mouse lacking SUR1-based K(ATP) channels. Stroke. 2003 Jan;34(1):164-70. Pubmed Sekine N, Ullrich S, Regazzi R, Pralong WF, Wollheim CB: Postreceptor signalling of growth hormone and prolactin and their effects in the differentiated insulin-secreting cell line, INS-1. Endocrinology. 1996 May;137(5):1841-50. Pubmed 4. Sodium/potassium-transporting ATPase alpha-1 chain Pharmacological action: unknown Actions: other This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients Organism class: human UniProt ID: P05023 Gene: ATP1A1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Lawrence CL, Rainbow RD, Davies NW, Standen NB: Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K(ATP) channels. Br J Pharmacol. 2002 Jul;136(5):746-52. Pubmed Guo W, Chen N, Chen Y, Xia Q, Shen Y: Activation of Mitochondrial ATP-Sensitive Potassium Channel Contributes to Protective Effect in Prolonged Myocardial Preservation. Conf Proc IEEE Eng Med Biol Soc. 2005;4:4027-30. Pubmed Comelli M, Metelli G, Mavelli I: Downmodulation of mitochondrial F0F1 ATP synthase by diazoxide in cardiac myoblasts: a dual effect of the drug. Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H820-9. Pubmed 5. Calcium-activated potassium channel subunit alpha 1 Pharmacological action: unknown Actions: other Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX) Organism class: human UniProt ID: Q12791 Gene: KCNMA1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Klockner U, Trieschmann U, Isenberg G: Pharmacological modulation of calcium and potassium channels in isolated vascular smooth muscle cells. Arzneimittelforschung. 1989 Jan;39(1A):120-6. Pubmed O’Malley D, Shanley LJ, Harvey J: Insulin inhibits rat hippocampal neurones via activation of ATP-sensitive K+ and large conductance Ca2+-activated K+ channels. Neuropharmacology. 2003 Jun;44(7):855-63. Pubmed Zhang L, Li X, Zhou R, Xing G: Possible role of potassium channel, big K in etiology of schizophrenia. Med Hypotheses. 2006;67(1):41-3. Epub 2006 Jan 30. Pubmed 6. Solute carrier family 12 member 3 Pharmacological action: unknown Actions: unknown Electrically silent transporter system. Mediates sodium and chloride reabsorption Organism class: human UniProt ID: P55017 Gene: SLC12A3 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

Targets

1. ATP-sensitive inward rectifier potassium channel 11

Pharmacological action: yes
Actions: inducer

This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium

Organism class: human
UniProt ID: Q14654 Link_out

Gene: KCNJ11 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

D’hahan N, Moreau C, Prost AL, Jacquet H, Alekseev AE, Terzic A, Vivaudou M: Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12162-7. Pubmed
Sakura H, Trapp S, Liss B, Ashcroft FM: Altered functional properties of KATP channel conferred by a novel splice variant of SUR1. J Physiol. 1999 Dec 1;521 Pt 2:337-50. Pubmed
Shindo T, Katayama Y, Horio Y, Kurachi Y: MCC-134, a novel vascular relaxing agent, is an inverse agonist for the pancreatic-type ATP-sensitive K(+) channel. J Pharmacol Exp Ther. 2000 Jan;292(1):131-5. Pubmed
de Lonlay P, Fournet JC, Touati G, Groos MS, Martin D, Sevin C, Delagne V, Mayaud C, Chigot V, Sempoux C, Brusset MC, Laborde K, Bellane-Chantelot C, Vassault A, Rahier J, Junien C, Brunelle F, Nihoul-Fekete C, Saudubray JM, Robert JJ: Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases. Eur J Pediatr. 2002 Jan;161(1):37-48. Pubmed
Russ U, Lange U, Loffler-Walz C, Hambrock A, Quast U: Binding and effect of K ATP channel openers in the absence of Mg2+. Br J Pharmacol. 2003 May;139(2):368-80. Pubmed

2. Carbonic anhydrase 1

Pharmacological action: yes
Actions: inhibitor

Reversible hydration of carbon dioxide

Organism class: human
UniProt ID: P00915 Link_out

Gene: CA1

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Domoki F, Bari F, Nagy K, Busija DW, Siklos L: Diazoxide prevents mitochondrial swelling and Ca2+ accumulation in CA1 pyramidal cells after cerebral ischemia in newborn pigs. Brain Res. 2004 Sep 3;1019(1-2):97-104. Pubmed
Erdemli G, Krnjevic K: Diazoxide suppresses slowly-inactivating outward and inward currents in CA1 hippocampal neurones. Neuroreport. 1993 Dec 13;5(3):249-51. Pubmed
Erdemli G, Krnjevic K: Actions of diazoxide on CA1 neurons in hippocampal slices from rats. Can J Physiol Pharmacol. 1995 May;73(5):608-18. Pubmed
Scuvee-Moreau J, Seutin V, Vrijens B, Pirotte B, De Tullio P, Massotte L, Albert A, Delarge J, Dresse A: Effect of potassium channel openers on the firing rate of hippocampal pyramidal cells and A10 dopaminergic neurons in vitro. Arch Physiol Biochem. 1997 Sep;105(5):421-8. Pubmed
Crepel V, Rovira C, Ben-Ari Y: The K+ channel opener diazoxide enhances glutamatergic currents and reduces GABAergic currents in hippocampal neurons. J Neurophysiol. 1993 Feb;69(2):494-503. Pubmed

3. Carbonic anhydrase 2

Pharmacological action: yes
Actions: inhibitor

Reversible hydration of carbon dioxide

Organism class: human
UniProt ID: P00918 Link_out

Gene: CA2

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Munoz A, Nakazaki M, Goodman JC, Barrios R, Onetti CG, Bryan J, Aguilar-Bryan L: Ischemic preconditioning in the hippocampus of a knockout mouse lacking SUR1-based K(ATP) channels. Stroke. 2003 Jan;34(1):164-70. Pubmed
Sekine N, Ullrich S, Regazzi R, Pralong WF, Wollheim CB: Postreceptor signalling of growth hormone and prolactin and their effects in the differentiated insulin-secreting cell line, INS-1. Endocrinology. 1996 May;137(5):1841-50. Pubmed

4. Sodium/potassium-transporting ATPase alpha-1 chain

Pharmacological action: unknown
Actions: other

This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients

Organism class: human
UniProt ID: P05023 Link_out

Gene: ATP1A1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Lawrence CL, Rainbow RD, Davies NW, Standen NB: Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K(ATP) channels. Br J Pharmacol. 2002 Jul;136(5):746-52. Pubmed
Guo W, Chen N, Chen Y, Xia Q, Shen Y: Activation of Mitochondrial ATP-Sensitive Potassium Channel Contributes to Protective Effect in Prolonged Myocardial Preservation. Conf Proc IEEE Eng Med Biol Soc. 2005;4:4027-30. Pubmed
Comelli M, Metelli G, Mavelli I: Downmodulation of mitochondrial F0F1 ATP synthase by diazoxide in cardiac myoblasts: a dual effect of the drug. Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H820-9. Pubmed

5. Calcium-activated potassium channel subunit alpha 1

Pharmacological action: unknown
Actions: other

Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX)

Organism class: human
UniProt ID: Q12791 Link_out

Gene: KCNMA1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Klockner U, Trieschmann U, Isenberg G: Pharmacological modulation of calcium and potassium channels in isolated vascular smooth muscle cells. Arzneimittelforschung. 1989 Jan;39(1A):120-6. Pubmed
O’Malley D, Shanley LJ, Harvey J: Insulin inhibits rat hippocampal neurones via activation of ATP-sensitive K+ and large conductance Ca2+-activated K+ channels. Neuropharmacology. 2003 Jun;44(7):855-63. Pubmed
Zhang L, Li X, Zhou R, Xing G: Possible role of potassium channel, big K in etiology of schizophrenia. Med Hypotheses. 2006;67(1):41-3. Epub 2006 Jan 30. Pubmed

6. Solute carrier family 12 member 3

Pharmacological action: unknown
Actions: unknown

Electrically silent transporter system. Mediates sodium and chloride reabsorption

Organism class: human
UniProt ID: P55017 Link_out

Gene: SLC12A3 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

Comments

Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:08

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.