Identification

Name
Mitiglinide
Accession Number
DB01252
Type
Small Molecule
Groups
Investigational
Description

Mitiglinide is a drug for the treatment of type 2 diabetes. Mitiglinide is thought to stimulate insulin secretion by closing the ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells.

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Mitiglinide calcium dihydrate9651C21W3Z207844-01-7QEVLNUAVAONTEW-UZYHXJQGSA-L
International/Other Brands
Glufast
Categories
UNII
D86I0XLB13
CAS number
145375-43-5
Weight
Average: 315.413
Monoisotopic: 315.183443669
Chemical Formula
C19H25NO3
InChI Key
WPGGHFDDFPHPOB-BBWFWOEESA-N
InChI
InChI=1S/C19H25NO3/c21-18(20-12-15-8-4-5-9-16(15)13-20)11-17(19(22)23)10-14-6-2-1-3-7-14/h1-3,6-7,15-17H,4-5,8-13H2,(H,22,23)/t15-,16+,17-/m0/s1
IUPAC Name
(2S)-4-[(3aR,7aS)-octahydro-1H-isoindol-2-yl]-2-benzyl-4-oxobutanoic acid
SMILES
[H][C@@](CC(=O)N1C[C@@]2([H])CCCC[C@@]2([H])C1)(CC1=CC=CC=C1)C(O)=O

Pharmacology

Indication

For the treatment of type 2 diabetes.

Pharmacodynamics

Mitiglinide belongs to the meglitinide class of blood glucose-lowering drugs. It is approved for use in Japan but has not yet gained FDA approval.

Mechanism of action

Mitiglinide is thought to stimulate insulin secretion by binding to and blocking ATP-sensitive K(+) (K(ATP)) channels (Kir6.2/SUR1 complex, KATP channels) in pancreatic beta-cells. Closure of potassium channels causes depolarization which stimulates calcium influx through voltage-gated calcium channels. High intracellular calcium subsequently triggers the exocytosis of insulin granules.

TargetActionsOrganism
AATP-binding cassette sub-family C member 8
inhibitor
Human
UPeroxisome proliferator-activated receptor gamma
agonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Mitiglinide is combined with 2,4-thiazolidinedione.
5-(2-methylpiperazine-1-sulfonyl)isoquinolineThe therapeutic efficacy of Mitiglinide can be increased when used in combination with 5-(2-methylpiperazine-1-sulfonyl)isoquinoline.
AcarboseThe risk or severity of hypoglycemia can be increased when Acarbose is combined with Mitiglinide.
AcetazolamideThe therapeutic efficacy of Mitiglinide can be increased when used in combination with Acetazolamide.
AcetohexamideThe risk or severity of hypoglycemia can be increased when Acetohexamide is combined with Mitiglinide.
Acetyl sulfisoxazoleThe therapeutic efficacy of Mitiglinide can be increased when used in combination with Acetyl sulfisoxazole.
Acetylsalicylic acidAcetylsalicylic acid may increase the hypoglycemic activities of Mitiglinide.
AgmatineThe risk or severity of hypoglycemia can be increased when Agmatine is combined with Mitiglinide.
AICA ribonucleotideThe risk or severity of hypoglycemia can be increased when Mitiglinide is combined with AICA ribonucleotide.
AlaproclateThe risk or severity of hypoglycemia can be increased when Alaproclate is combined with Mitiglinide.
Food Interactions
Not Available

References

General References
Not Available
External Links
KEGG Drug
D01854
PubChem Compound
121891
PubChem Substance
46506527
ChemSpider
108739
ChEBI
135349
ChEMBL
CHEMBL471498
Therapeutic Targets Database
DAP000917
PharmGKB
PA164748124
Wikipedia
Mitiglinide
ATC Codes
A10BX08 — Mitiglinide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of ASP1941 / Pharmacokinetics of Mitiglinide1
1CompletedTreatmentType 2 Diabetes Mellitus1
3CompletedTreatmentDiabetes Mellitus (DM)1
3CompletedTreatmentType 2 Diabetes Mellitus3
4Active Not RecruitingTreatmentBMI >27 kg/m2 / BMI >30 kg/m2 / Masked Hypertension / Type 2 Diabetes Mellitus1
4CompletedNot AvailableType 2 Diabetes Mellitus1
4CompletedTreatmentType 2 Diabetes Mellitus2

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP2.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0708 mg/mLALOGPS
logP3.17ALOGPS
logP2.92ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)4.62ChemAxon
pKa (Strongest Basic)-0.83ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area57.61 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity88.31 m3·mol-1ChemAxon
Polarizability34.98 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9921
Blood Brain Barrier+0.9694
Caco-2 permeable-0.5956
P-glycoprotein substrateSubstrate0.5
P-glycoprotein inhibitor INon-inhibitor0.6887
P-glycoprotein inhibitor IINon-inhibitor0.8357
Renal organic cation transporterInhibitor0.5235
CYP450 2C9 substrateNon-substrate0.8241
CYP450 2D6 substrateNon-substrate0.6396
CYP450 3A4 substrateNon-substrate0.5135
CYP450 1A2 substrateNon-inhibitor0.765
CYP450 2C9 inhibitorNon-inhibitor0.8653
CYP450 2D6 inhibitorNon-inhibitor0.9234
CYP450 2C19 inhibitorNon-inhibitor0.6464
CYP450 3A4 inhibitorNon-inhibitor0.8786
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8753
Ames testNon AMES toxic0.7059
CarcinogenicityNon-carcinogens0.95
BiodegradationReady biodegradable0.522
Rat acute toxicity2.3334 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8826
hERG inhibition (predictor II)Non-inhibitor0.7529
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 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 phenylpropanoic acids. These are compounds with a structure containing a benzene ring conjugated to a propanoic acid.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Phenylpropanoic acids
Sub Class
Not Available
Direct Parent
Phenylpropanoic acids
Alternative Parents
Isoindolines / Isoindoles / N-acylpyrrolidines / Benzene and substituted derivatives / Tertiary carboxylic acid amides / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds
show 3 more
Substituents
3-phenylpropanoic-acid / Isoindoline / Isoindole / Isoindole or derivatives / N-acylpyrrolidine / Monocyclic benzene moiety / Benzenoid / Tertiary carboxylic acid amide / Pyrrolidine / Carboxamide group
show 14 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. Sunaga Y, Gonoi T, Shibasaki T, Ichikawa K, Kusama H, Yano H, Seino S: The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide. Eur J Pharmacol. 2001 Nov 9;431(1):119-25. [PubMed:11716850]
  2. Nagamatsu S, Ohara-Imaizumi M, Nakamichi Y, Kikuta T, Nishiwaki C: Imaging docking and fusion of insulin granules induced by antidiabetes agents: sulfonylurea and glinide drugs preferentially mediate the fusion of newcomer, but not previously docked, insulin granules. Diabetes. 2006 Oct;55(10):2819-25. [PubMed:17003348]
  3. Ogawa K, Ikewaki K, Taniguchi I, Takatsuka H, Mori C, Sasaki H, Okazaki F, Shimizu M, Mochizuki S: Mitiglinide, a novel oral hypoglycemic agent, preserves the cardioprotective effect of ischemic preconditioning in isolated perfused rat hearts. Int Heart J. 2007 May;48(3):337-45. [PubMed:17592198]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE...
Gene Name
PPARG
Uniprot ID
P37231
Uniprot Name
Peroxisome proliferator-activated receptor gamma
Molecular Weight
57619.58 Da
References
  1. Scarsi M, Podvinec M, Roth A, Hug H, Kersten S, Albrecht H, Schwede T, Meyer UA, Rucker C: Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Mol Pharmacol. 2007 Feb;71(2):398-406. Epub 2006 Nov 2. [PubMed:17082235]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [PubMed:19515014]

Drug created on March 30, 2007 12:07 / Updated on November 02, 2018 08:58