Banner
targets (6) enzymes (1)
for drugs
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 Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Dizoxide
Eudemine
Hyperstat
Hypertonalum
Mutabase
Proglicem
Proglycem
Brand 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
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 330.5 °C PhysProp
water solubility 2850 mg/L Not Available
logP 1.20 HANSCH,C ET AL. (1995)
pKa 8.74 SANGSTER (1994)
Predicted Properties
Property Value Source
water solubility 5.52e-01 g/l ALOGPS
logP 1.09 ALOGPS
logP 1 ChemAxon
logS -2.6 ALOGPS
pKa (strongest acidic) 10.48 ChemAxon
pKa (strongest basic) 1.33 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 58.53 ChemAxon
rotatable bond count 0 ChemAxon
refractivity 54.84 ChemAxon
polarizability 20.98 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00294 Link_out
KEGG Compound C06949 Link_out
PubChem Compound 3019 Link_out
PubChem Substance 46508027 Link_out
ChemSpider 2911 Link_out
ChEBI 4495 Link_out
ChEMBL 4495 Link_out
Therapeutic Targets Database DAP000956 Link_out
PharmGKB PA449285 Link_out
IUPHAR 2409 Link_out
Guide to Pharmacology 2409 Link_out
Drug Product Database 503347 Link_out
Drugs.com http://www.drugs.com/cdi/diazoxide-suspension.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Diazoxide Link_out
ATC Codes
  • C02DA01
  • V03AH01
AHFS Codes
  • 24:08.20
PDB Entries Not Available
FDA label Not Available
MSDS show (73 KB)
Interactions
Drug Interactions
Drug Interaction
Bendroflumethiazide Significant hyperglycemic effect
Chlorpropamide Antagonism.
Chlorthalidone Significant hyperglycemic effect
Fosphenytoin Diazoxide decreases the hydantoin effect
Glyburide Antagonism.
Hydrochlorothiazide Significant hyperglycemic effect
Indapamide Significant hyperglycemic effect
Phenytoin Diazoxide decreases the efficacy of phenytoin.
Trandolapril Diazoxide may increase the hypotensive effect of Trandolapril. Monitor for changes in blood pressure.
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 Link_out
Gene: KCNJ11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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
  2. 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
  3. 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
  4. 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
  5. 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 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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
  2. 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
  3. 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
  4. 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
  5. 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 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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
  2. 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:
  1. 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
  2. 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
  3. 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:
  1. 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
  2. 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
  3. 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:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. 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
Enzymes

1. Glutamine synthetase

Actions: inhibitor

ATP + L-glutamate + NH(3) = ADP + phosphate + L-glutamine

UniProt ID: P15104 Link_out
Gene: GLUL Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Velloso LA, Bjork E, Ballagi AE, Funa K, Andersson A, Kampe O, Karlsson FA, Eizirik DL: Regulation of GAD expression in islets of Langerhans occurs both at the mRNA and protein level. Mol Cell Endocrinol. 1994 Jun;102(1-2):31-7. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19