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Identification
NameDiazoxide
Accession NumberDB01119  (APRD00914)
Typesmall molecule
Groupsapproved
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
Synonyms
SynonymLanguageCode
DiazossidoNot AvailableNot Available
DiazoxideNot AvailableNot Available
DiazoxidoNot AvailableNot Available
DiazoxidumNot AvailableNot Available
EudemineNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
EudemineMercury
HyperstatSchering
ProglycemGate
Brand mixturesNot Available
Categories
CAS number364-98-7
WeightAverage: 230.671
Monoisotopic: 229.991675875
Chemical FormulaC8H7ClN2O2S
InChI KeyGDLBFKVLRPITMI-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)
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassThiadiazines
SubclassBenzothiadiazines
Direct parentBenzothiadiazines
Alternative parentsChlorobenzenes; Aryl Chlorides; Sulfonic Acids and Derivatives; Polyamines; Organochlorides
Substituentschlorobenzene; aryl chloride; benzene; aryl halide; sulfonic acid derivative; polyamine; organochloride; organohalogen; organonitrogen compound
Classification descriptionThis compound belongs to the benzothiadiazines. These are organic compounds containing a benzene fused to a thiadiazine ring (a six-member ring with two nitrogen atoms and a sulfur atom).
Pharmacology
IndicationUsed parentally to treat hypertensive emergencies. Also used to treat hypoglycemia secondary to insulinoma.
PharmacodynamicsDiazoxide 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 actionAs 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.
AbsorptionReadily absorbed following oral administration.
Volume of distributionNot Available
Protein bindingVery high (more than 90%) to serum proteins.
Metabolism

Hepatic.

Route of eliminationProglycem is extensively bound (more than 90%) to serum proteins, and is excreted in the kidneys.
Half life28 ±8.3 hours in normal adults.
ClearanceNot Available
ToxicityOral LD50 in rat and mouse: 980 mg/kg and 444 mg/kg, respectively.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.5923
Caco-2 permeable - 0.5765
P-glycoprotein substrate Non-substrate 0.6817
P-glycoprotein inhibitor I Non-inhibitor 0.6924
P-glycoprotein inhibitor II Non-inhibitor 0.6927
Renal organic cation transporter Non-inhibitor 0.8107
CYP450 2C9 substrate Non-substrate 0.5606
CYP450 2D6 substrate Non-substrate 0.8064
CYP450 3A4 substrate Non-substrate 0.5774
CYP450 1A2 substrate Inhibitor 0.9108
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Inhibitor 0.8932
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.831
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7977
Ames test Non AMES toxic 0.7888
Carcinogenicity Non-carcinogens 0.8304
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.3408 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9233
hERG inhibition (predictor II) Non-inhibitor 0.9271
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
FormRouteStrength
CapsuleOral
Prices
Unit descriptionCostUnit
Proglycem 50 mg/ml Suspension 30ml Bottle197.05USDbottle
Diazoxide powder85.07USDg
Proglycem 100 mg Capsule1.65USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point330Topliss, J.G., Sperber, N. and Rubin, A.A.; U.S. Patent 2,986,573; May 30, 1961; assigned to Schering Corporation. Topliss, J.G., Sperber, N. and Rubin, A.A.; U.S. Patent 3,345,365; October 3, 1967; assigned to Schering Corporation.
water solubility2850 mg/LNot Available
logP1.20HANSCH,C ET AL. (1995)
pKa8.74SANGSTER (1994)
Predicted Properties
PropertyValueSource
water solubility5.52e-01 g/lALOGPS
logP1.09ALOGPS
logP1ChemAxon
logS-2.6ALOGPS
pKa (strongest acidic)10.48ChemAxon
pKa (strongest basic)1.33ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count1ChemAxon
polar surface area58.53ChemAxon
rotatable bond count0ChemAxon
refractivity54.84ChemAxon
polarizability20.98ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Topliss, J.G., Sperber, N. and Rubin, A.A.; U.S. Patent 2,986,573; May 30, 1961; assigned
to Schering Corporation.
Topliss, J.G., Sperber, N. and Rubin, A.A.; U.S. Patent 3,345,365; October 3, 1967; assigned
to Schering Corporation.

General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00294
KEGG CompoundC06949
PubChem Compound3019
PubChem Substance46508027
ChemSpider2911
ChEBI4495
ChEMBLCHEMBL181
Therapeutic Targets DatabaseDAP000956
PharmGKBPA449285
IUPHAR2409
Guide to Pharmacology2409
Drug Product Database503347
Drugs.comhttp://www.drugs.com/cdi/diazoxide-suspension.html
WikipediaDiazoxide
ATC CodesC02DA01V03AH01
AHFS Codes
  • 24:08.20
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(73 KB)
Interactions
Drug Interactions
Drug
BendroflumethiazideSignificant hyperglycemic effect
ChlorpropamideAntagonism.
ChlorthalidoneSignificant hyperglycemic effect
FosphenytoinDiazoxide decreases the hydantoin effect
GlyburideAntagonism.
HydrochlorothiazideSignificant hyperglycemic effect
IndapamideSignificant hyperglycemic effect
PhenytoinDiazoxide decreases the efficacy of phenytoin.
TrandolaprilDiazoxide may increase the hypotensive effect of Trandolapril. Monitor for changes in blood pressure.
Food InteractionsNot Available

Targets

1. ATP-sensitive inward rectifier potassium channel 11

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inducer

Components

Name UniProt ID Details
ATP-sensitive inward rectifier potassium channel 11 Q14654 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 1 P00915 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Carbonic anhydrase 2 P00918 Details

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 subunit alpha-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other

Components

Name UniProt ID Details
Sodium/potassium-transporting ATPase subunit alpha-1 P05023 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other

Components

Name UniProt ID Details
Calcium-activated potassium channel subunit alpha-1 Q12791 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: unknown

Components

Name UniProt ID Details
Solute carrier family 12 member 3 P55017 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Glutamine synthetase P15104 Details

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

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Drug created on June 13, 2005 07:24 / Updated on April 11, 2014 14:53