Identification

Name
Gliquidone
Accession Number
DB01251
Type
Small Molecule
Groups
Approved, Investigational
Description

Gliquidone is an anti-diabetic drug in the sulfonylurea class. It is used in the treatment of diabetes mellitus type 2. It is an ATP-dependent K+ (KATP) channel blocker. This block causes a depolarization which leads to activation of voltage-dependent Ca channels and Ca2+ influx, and eventually increases insulin release.

Structure
Thumb
Synonyms
  • Gliquidona
  • Glurenorm
External IDs
ARDF 26
International/Other Brands
Devotan (Menarini) / Fordiab (Hexpharm Jaya) / Glidiab (Soho) / Glunormal (Ying Yuan) / Glurenor (Guidotti) / Glurenorm (Boehringer Ingelheim) / Jie Shi (Tianjin Institute of Pharmaceutical Research Pharmaceutical) / Ka Rui Lin (Anjielun) / Lodem (Dexa Medica)
Categories
UNII
C7C2QDD75P
CAS number
33342-05-1
Weight
Average: 527.632
Monoisotopic: 527.209006493
Chemical Formula
C27H33N3O6S
InChI Key
LLJFMFZYVVLQKT-UHFFFAOYSA-N
InChI
InChI=1S/C27H33N3O6S/c1-27(2)23-14-11-20(36-3)17-22(23)24(31)30(25(27)32)16-15-18-9-12-21(13-10-18)37(34,35)29-26(33)28-19-7-5-4-6-8-19/h9-14,17,19H,4-8,15-16H2,1-3H3,(H2,28,29,33)
IUPAC Name
1-cyclohexyl-3-{4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]benzenesulfonyl}urea
SMILES
COC1=CC2=C(C=C1)C(C)(C)C(=O)N(CCC1=CC=C(C=C1)S(=O)(=O)NC(=O)NC1CCCCC1)C2=O

Pharmacology

Indication

Used in the treatment of diabetes mellitus type 2.

Pharmacodynamics

Gliquidone is an anti-diabetic drug in the sulfonylurea class. In patients with diabetes mellitus, there is a deficiency or absence of a hormone manufactured by the pancreas called insulin. Insulin is the main hormone responsible for the control of sugar in the blood. Gliquidone is an antidiabetic medication which is used in those patients with adult maturity onset or non-insulin dependent diabetes (NIDDM). It works by lowering blood sugar levels by stimulating the production and release of insulin from the pancreas. It also promotes the movement of sugar from the blood into the cells in the body which need it.

Mechanism of action

The mechanism of action of gliquidone in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells, and increasing sensitivity of peripheral tissues to insulin. Gliquidone likely binds to ATP-sensitive potassium channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Membrane depolarization stimulates calcium ion influx through voltage-sensitive calcium channels. This increase in intracellular calcium ion concentration induces the secretion of insulin.

TargetActionsOrganism
AATP-binding cassette sub-family C member 8
inhibitor
Human
AATP-sensitive inward rectifier potassium channel 8
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

The mean terminal half-life was approximately 8 hours (range 5.7-9.4 hours)

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinGliquidone may increase the anticoagulant activities of (R)-warfarin.
(S)-WarfarinGliquidone may increase the anticoagulant activities of (S)-Warfarin.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Gliquidone is combined with 2,4-thiazolidinedione.
4-hydroxycoumarinGliquidone may increase the anticoagulant activities of 4-hydroxycoumarin.
5-(2-methylpiperazine-1-sulfonyl)isoquinolineThe therapeutic efficacy of Gliquidone can be increased when used in combination with 5-(2-methylpiperazine-1-sulfonyl)isoquinoline.
AbirateroneThe metabolism of Gliquidone can be decreased when combined with Abiraterone.
AcarboseThe risk or severity of hypoglycemia can be increased when Acarbose is combined with Gliquidone.
AcebutololAcebutolol may increase the hypoglycemic activities of Gliquidone.
AceclofenacThe metabolism of Aceclofenac can be decreased when combined with Gliquidone.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Gliquidone.
Food Interactions
Not Available

References

Synthesis Reference

U.S. Patent 3,708,486.

General References
Not Available
External Links
Human Metabolome Database
HMDB0015381
KEGG Drug
D02430
PubChem Compound
91610
PubChem Substance
46508425
ChemSpider
82719
ChEBI
93416
ChEMBL
CHEMBL383634
Therapeutic Targets Database
DAP000924
PharmGKB
PA164744895
Wikipedia
Gliquidone
ATC Codes
A10BB08 — Gliquidone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentDiabetes Mellitus (DM) / Type 2 Diabetes Mellitus1
Not AvailableCompletedNot AvailableType 2 Diabetes Mellitus3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)180-182U.S. Patent 3,708,486.
logP4.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0022 mg/mLALOGPS
logP3.59ALOGPS
logP4.14ChemAxon
logS-5.4ALOGPS
pKa (Strongest Acidic)4.32ChemAxon
pKa (Strongest Basic)-4.8ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area121.88 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity139.48 m3·mol-1ChemAxon
Polarizability57.26 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9157
Blood Brain Barrier+0.625
Caco-2 permeable-0.6185
P-glycoprotein substrateSubstrate0.7457
P-glycoprotein inhibitor IInhibitor0.6115
P-glycoprotein inhibitor IIInhibitor0.805
Renal organic cation transporterNon-inhibitor0.7921
CYP450 2C9 substrateSubstrate0.5166
CYP450 2D6 substrateNon-substrate0.8162
CYP450 3A4 substrateSubstrate0.594
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.6454
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorInhibitor0.7961
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5173
Ames testNon AMES toxic0.6124
CarcinogenicityNon-carcinogens0.7477
BiodegradationNot ready biodegradable0.8693
Rat acute toxicity2.3506 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8418
hERG inhibition (predictor II)Inhibitor0.6182
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
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udi-0000190000-4154029e3d9f7cf38376
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udi-0422900000-64e5b1e1949d772ce08b

Taxonomy

Description
This compound belongs to the class of organic compounds known as 1,3-isoquinolinediones. These are isoquinoline derivatives carrying one C=O group at positions 1, and 3 respectively.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Isoquinolines and derivatives
Sub Class
1,3-isoquinolinediones
Direct Parent
1,3-isoquinolinediones
Alternative Parents
Isoquinolones and derivatives / Tetrahydroisoquinolines / Benzenesulfonamides / Benzenesulfonyl compounds / Anisoles / Sulfonylureas / Alkyl aryl ethers / N-substituted carboxylic acid imides / Organosulfonic acids and derivatives / Aminosulfonyl compounds
show 8 more
Substituents
1,3-isoquinolinedione / Isoquinolone / Tetrahydroisoquinoline / Benzenesulfonamide / Benzenesulfonyl group / Anisole / Alkyl aryl ether / Sulfonylurea / Monocyclic benzene moiety / Benzenoid
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Sulfonylurea receptor activity
Specific Function
Subunit of the beta-cell ATP-sensitive potassium channel (KATP). Regulator of ATP-sensitive K(+) channels and insulin release.
Gene Name
ABCC8
Uniprot ID
Q09428
Uniprot Name
ATP-binding cassette sub-family C member 8
Molecular Weight
176990.36 Da
References
  1. Gribble FM, Ashcroft FM: Sulfonylurea sensitivity of adenosine triphosphate-sensitive potassium channels from beta cells and extrapancreatic tissues. Metabolism. 2000 Oct;49(10 Suppl 2):3-6. [PubMed:11078468]
  2. Harrower A: Gliclazide modified release: from once-daily administration to 24-hour blood glucose control. Metabolism. 2000 Oct;49(10 Suppl 2):7-11. [PubMed:11078469]
  3. Lawrence CL, Proks P, Rodrigo GC, Jones P, Hayabuchi Y, Standen NB, Ashcroft FM: Gliclazide produces high-affinity block of KATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells. Diabetologia. 2001 Aug;44(8):1019-25. [PubMed:11484080]
  4. Reimann F, Ashcroft FM, Gribble FM: Structural basis for the interference between nicorandil and sulfonylurea action. Diabetes. 2001 Oct;50(10):2253-9. [PubMed:11574406]
  5. Proks P, Reimann F, Green N, Gribble F, Ashcroft F: Sulfonylurea stimulation of insulin secretion. Diabetes. 2002 Dec;51 Suppl 3:S368-76. [PubMed:12475777]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Inward rectifier potassium channel activity
Specific Function
This potassium channel 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...
Gene Name
KCNJ8
Uniprot ID
Q15842
Uniprot Name
ATP-sensitive inward rectifier potassium channel 8
Molecular Weight
47967.455 Da
References
  1. Szewczyk A, Wojcik G, Lobanov NA, Nalecz MJ: The mitochondrial sulfonylurea receptor: identification and characterization. Biochem Biophys Res Commun. 1997 Jan 23;230(3):611-5. [PubMed:9015372]
  2. Sato T, Costa AD, Saito T, Ogura T, Ishida H, Garlid KD, Nakaya H: Bepridil, an antiarrhythmic drug, opens mitochondrial KATP channels, blocks sarcolemmal KATP channels, and confers cardioprotection. J Pharmacol Exp Ther. 2006 Jan;316(1):182-8. Epub 2005 Sep 20. [PubMed:16174795]
  3. Hill RA, Rudra S, Peng B, Roane DS, Bounds JK, Zhang Y, Adloo A, Lu T: Hydroxyl-substituted sulfonylureas as potent inhibitors of specific [3H]glyburide binding to rat brain synaptosomes. Bioorg Med Chem. 2003 May 1;11(9):2099-113. [PubMed:12670661]

Enzymes

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]

Drug created on March 30, 2007 08:35 / Updated on November 05, 2018 17:48