Identification

Name
Acetohexamide
Accession Number
DB00414  (APRD00773)
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

A sulfonylurea hypoglycemic agent that is metabolized in the liver to 1-hydrohexamide. Acetohexamide has been discontinued in the US market.

Structure
Thumb
Synonyms
  • 1-((p-Acetylphenyl)sulfonyl)-3-cyclohexylurea
  • 1-[(4-acetylbenzene)sulfonyl]-3-cyclohexylurea 4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide
  • Acetohexamid
  • Acetohexamida
  • Acétohexamide
  • Acetohexamide
  • Acetohexamidum
  • N-(p-Acetylphenylsulfonyl)-N'-cyclohexylurea
External IDs
33006
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Dimelor Tablet 1843 500mgTablet500 mgOralEli Lilly & Co. Ltd.1963-12-311998-08-04Canada
International/Other Brands
Acetohexamide (Watson) / Dimelin (Shionogi Seiyaku) / Dymelor (Lilly) / Gamadiabet (Salvat)
Categories
UNII
QGC8W08I6I
CAS number
968-81-0
Weight
Average: 324.395
Monoisotopic: 324.114377828
Chemical Formula
C15H20N2O4S
InChI Key
VGZSUPCWNCWDAN-UHFFFAOYSA-N
InChI
InChI=1S/C15H20N2O4S/c1-11(18)12-7-9-14(10-8-12)22(20,21)17-15(19)16-13-5-3-2-4-6-13/h7-10,13H,2-6H2,1H3,(H2,16,17,19)
IUPAC Name
3-(4-acetylbenzenesulfonyl)-1-cyclohexylurea
SMILES
CC(=O)C1=CC=C(C=C1)S(=O)(=O)NC(=O)NC1CCCCC1

Pharmacology

Indication

Used in the management of diabetes mellitus type 2 (adult-onset).

Pharmacodynamics

Acetohexamide is an intermediate-acting, first-generation oral sulfonylurea. It lowers blood sugar by stimulating the pancreatic beta cells to secrete insulin and by helping the body use insulin efficiently. The pancreas must produce insulin for this medication to work. Acetohexamide has one-third the potency of chlorpropamide, and twice the potency of tolbutamide; however, similar hypoglycemic efficacy occurs with equipotent dosage of sulfonylureas.

Mechanism of action

Sulfonylureas such as acetohexamide bind to an ATP-dependent K+ channel on the cell membrane of pancreatic beta cells. This inhibits a tonic, hyperpolarizing outflux of potassium, which causes the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca2+ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin.

TargetActionsOrganism
AATP-sensitive inward rectifier potassium channel 1
inhibitor
Human
Absorption

Rapidly absorbed from the GI tract.

Volume of distribution
Not Available
Protein binding

90%

Metabolism

Extensively metabolized in the liver to the active metabolite hydroxyhexamide, which exhibits greater hypoglycemic potency than acetohexamide. Hydroxyhexamide is believed to be responsible for prolonged hypoglycemic effects.

Route of elimination
Not Available
Half life

Elimination half-life of the parent compound is 1.3 hours and the elimination half-life of the active metabolite is approximately 5-6 hours.

Clearance
Not Available
Toxicity

Oral, rat LD50: 5 gm/kg; Oral, mouse LD50: >2500 mg/kg. Symptoms of an acetohexamide overdose include hunger, nausea, anxiety, cold sweats, weakness, drowsiness, unconsciousness, and coma.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololAcebutolol may increase the hypoglycemic activities of Acetohexamide.
AcenocoumarolAcetohexamide may increase the anticoagulant activities of Acenocoumarol.
AcetazolamideThe therapeutic efficacy of Acetohexamide can be increased when used in combination with Acetazolamide.
Acetylsalicylic acidAcetylsalicylic acid may increase the hypoglycemic activities of Acetohexamide.
AlbiglutideAlbiglutide may increase the hypoglycemic activities of Acetohexamide.
AlogliptinAlogliptin may increase the hypoglycemic activities of Acetohexamide.
AlprenololAlprenolol may increase the hypoglycemic activities of Acetohexamide.
Aluminium clofibrateAluminium clofibrate may increase the hypoglycemic activities of Acetohexamide.
AmcinonideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Amcinonide.
Aminosalicylic AcidAminosalicylic Acid may increase the hypoglycemic activities of Acetohexamide.
Food Interactions
  • Avoid alcohol.
  • Take without regard to meals.

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0014558
KEGG Drug
D00219
KEGG Compound
C06806
PubChem Compound
1989
PubChem Substance
46505821
ChemSpider
1912
ChEBI
28052
ChEMBL
CHEMBL1589
Therapeutic Targets Database
DAP000922
PharmGKB
PA164777011
Drugs.com
Drugs.com Drug Page
Wikipedia
Acetohexamide
ATC Codes
A10BB31 — Acetohexamide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentImpaired Glucose Tolerance (IGT) / Type 2 Diabetes Mellitus1
Not AvailableCompletedNot AvailableType 2 Diabetes Mellitus3

Pharmacoeconomics

Manufacturers
  • Barr laboratories inc
  • Usl pharma inc
  • Watson laboratories inc
  • Eli lilly industries inc
Packagers
  • Barr Pharmaceuticals
  • Murfreesboro Pharmaceutical Nursing Supply
Dosage forms
FormRouteStrength
TabletOral500 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)188-190 °CSigal,M.V.,Jr.andVanArendonk,A.M.; US.Patent3,320,312;May16,1967;assigned to Eli Lilly and Company.
water solubility3430 mg/L (at 37 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP2.44SANGSTER (1993)
logS-2.06ADME Research, USCD
Predicted Properties
PropertyValueSource
Water Solubility0.0483 mg/mLALOGPS
logP1.72ALOGPS
logP1.81ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)4.31ChemAxon
pKa (Strongest Basic)-7.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area92.34 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity82.77 m3·mol-1ChemAxon
Polarizability33.97 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9425
Blood Brain Barrier+0.8308
Caco-2 permeable-0.6272
P-glycoprotein substrateNon-substrate0.6406
P-glycoprotein inhibitor INon-inhibitor0.8731
P-glycoprotein inhibitor IINon-inhibitor0.8808
Renal organic cation transporterNon-inhibitor0.8538
CYP450 2C9 substrateSubstrate0.6473
CYP450 2D6 substrateNon-substrate0.8795
CYP450 3A4 substrateNon-substrate0.7171
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5913
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.8447
BiodegradationNot ready biodegradable0.8033
Rat acute toxicity2.1793 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8799
hERG inhibition (predictor II)Non-inhibitor0.8982
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-03di-8390000000-581eca2d35a4f5f0362a
GC-MS Spectrum - EI-BGC-MSsplash10-0a5c-9200000000-09e03cfa3bf5df8c2b45
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as alkyl-phenylketones. These are aromatic compounds containing a ketone substituted by one alkyl group, and a phenyl group.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbonyl compounds
Direct Parent
Alkyl-phenylketones
Alternative Parents
Benzenesulfonamides / Benzenesulfonyl compounds / Acetophenones / Benzoyl derivatives / Aryl alkyl ketones / Sulfonylureas / Organosulfonic acids and derivatives / Aminosulfonyl compounds / Propargyl-type 1,3-dipolar organic compounds / Carboximidic acids and derivatives
show 3 more
Substituents
Alkyl-phenylketone / Benzenesulfonamide / Acetophenone / Benzenesulfonyl group / Benzoyl / Aryl alkyl ketone / Sulfonylurea / Benzenoid / Monocyclic benzene moiety / Aminosulfonyl compound
show 13 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
N-sulfonylurea, acetophenones (CHEBI:28052)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Phosphatidylinositol-4,5-bisphosphate binding
Specific Function
In the kidney, probably plays a major role in potassium homeostasis. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than...
Gene Name
KCNJ1
Uniprot ID
P48048
Uniprot Name
ATP-sensitive inward rectifier potassium channel 1
Molecular Weight
44794.6 Da
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:17139284]
  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:17016423]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Prostaglandin-e2 9-reductase activity
Specific Function
NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. ...
Gene Name
CBR1
Uniprot ID
P16152
Uniprot Name
Carbonyl reductase [NADPH] 1
Molecular Weight
30374.73 Da
References
  1. Imamura Y, Shimada H: Differential pharmacokinetics of acetohexamide in male Wistar-Imamichi and Sprague-Dawley rats: role of microsomal carbonyl reductase. Biol Pharm Bull. 2005 Jan;28(1):185-7. [PubMed:15635190]
  2. Imamura Y, Koga T, Higuchi T, Otagiri M, Sugino E, Hibino S: Inhibitory effect of drugs with a ketone group on reduction of acetohexamide catalyzed by carbonyl reductase from rabbit kidney. J Enzyme Inhib. 1997 Feb;11(4):285-92. [PubMed:9208371]
  3. Kishimoto M, Kawamori R, Kamada T, Inaba T: Carbonyl reductase activity for acetohexamide in human erythrocytes. Drug Metab Dispos. 1994 May-Jun;22(3):367-70. [PubMed:8070312]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. May M, Schindler C: Clinically and pharmacologically relevant interactions of antidiabetic drugs. Ther Adv Endocrinol Metab. 2016 Apr;7(2):69-83. doi: 10.1177/2042018816638050. Epub 2016 Mar 31. [PubMed:27092232]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Joseph KS, Hage DS: Characterization of the binding of sulfonylurea drugs to HSA by high-performance affinity chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Jun 1;878(19):1590-8. doi: 10.1016/j.jchromb.2010.04.019. [PubMed:20435530]
  2. Joseph KS, Anguizola J, Jackson AJ, Hage DS: Chromatographic analysis of acetohexamide binding to glycated human serum albumin. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Oct 15;878(28):2775-81. doi: 10.1016/j.jchromb.2010.08.021. Epub 2010 Aug 21. [PubMed:20829128]
  3. Yoo MJ, Hage DS: Use of peak decay analysis and affinity microcolumns containing silica monoliths for rapid determination of drug-protein dissociation rates. J Chromatogr A. 2011 Apr 15;1218(15):2072-8. doi: 10.1016/j.chroma.2010.09.070. Epub 2010 Oct 16. [PubMed:20956006]
  4. Basiaga SB, Hage DS: Chromatographic studies of changes in binding of sulfonylurea drugs to human serum albumin due to glycation and fatty acids. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Nov 15;878(30):3193-7. doi: 10.1016/j.jchromb.2010.09.033. Epub 2010 Oct 23. [PubMed:20974553]
  5. Tong Z, Joseph KS, Hage DS: Detection of heterogeneous drug-protein binding by frontal analysis and high-performance affinity chromatography. J Chromatogr A. 2011 Dec 9;1218(49):8915-24. doi: 10.1016/j.chroma.2011.04.078. Epub 2011 May 6. [PubMed:21612784]

Drug created on June 13, 2005 07:24 / Updated on October 01, 2018 12:47