Lobeglitazone

Identification

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Name

Lobeglitazone

Accession Number

DB09198

Type

Small Molecule

Groups

Experimental

Description

Lobeglitazone is an antidiabetic medication from the thiazolidinedione class of drugs. It primarily functions as an insulin sensitizer by binding and activating Peroxisome Proliferator-Activated Receptors (PPAR) gamma within fat cells. By activating PPAR-gamma and promoting the binding of insulin at fat cells, lobeglitazone thereby has been shown to reduce blood sugar levels, lower hemoglobain A1C (HbA1C) levels, and improve lipid and liver profiles ¹. Unlike Pioglitazone, which is a dual PPAR agonist at PPAR-alpha and PPAR-gamma, Lobeglitazone is a pure PPAR-alpha agonist.

Lobeglitazone was approved by the Ministry of Food and Drug Safety (South Korea) in 2013, and is being monitored by postmarketing surveillance until 2019. Lobeglitazone is not approved for use by either the Food and Drug Administration (USA), Health Canada, or by the European Medicines Agency for use in the management of diabetes.

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Lobeglitazone (DB09198)

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Synonyms

Not Available

External IDs

CKD 501 / CKD-501 / CKD501

Product Ingredients

Ingredient	UNII	CAS	InChI Key
lobeglitazone sulfate	95C712E83P	Not Available	Not applicable

International/Other Brands

Duvie (Chong Kun Dang)

Categories

• Blood Glucose Lowering Agents
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (moderate)
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 inhibitors (unknown strength)
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A4 Substrates (strength unknown)
• Cytochrome P-450 Enzyme Inhibitors
• OATP1B1/SLCO1B1 Inhibitors
• PPAR alpha, agonists
• PPAR gamma, agonists
• Sulfur Compounds
• Thiazoles
• Thiazolidinediones

UNII

MY89F08K5D

CAS number

607723-33-1

Weight

Average: 480.54
Monoisotopic: 480.146741063

Chemical Formula

C₂₄H₂₄N₄O₅S

InChI Key

CHHXEZSCHQVSRE-UHFFFAOYSA-N

InChI

InChI=1S/C24H24N4O5S/c1-28(21-14-22(26-15-25-21)33-19-9-7-17(31-2)8-10-19)11-12-32-18-5-3-16(4-6-18)13-20-23(29)27-24(30)34-20/h3-10,14-15,20H,11-13H2,1-2H3,(H,27,29,30)

IUPAC Name

5-{[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl](methyl)amino}ethoxy)phenyl]methyl}-1,3-thiazolidine-2,4-dione

SMILES

COC1=CC=C(OC2=NC=NC(=C2)N(C)CCOC2=CC=C(CC3SC(=O)NC3=O)C=C2)C=C1

Pharmacology

Indication

Lobeglitazone was approved by the Ministry of Food and Drug Safety (South Korea) in 2013, and is being monitored by postmarketing surveillance until 2019. Lobeglitazone is not approved for use by either the Food and Drug Administration (USA), Health Canada, or by the European Medicines Agency for use in the management of diabetes.

Pharmacodynamics

Not Available

Mechanism of action

Lobeglitazone acts as an insulin sensitizer by binding and activating Peroxisome Proliferator-Activated Receptors (PPAR) gamma within fat cells. By promoting the binding of insulin at fat cells, lobeglitazone has been shown to reduce blood sugar levels, lower hemoglobain A1C (HbA1C) levels, and improve lipid and liver profiles ¹. Unlike Pioglitazone, which is a dual PPAR agonist at PPAR-alpha and PPAR-gamma, Lobeglitazone is a pure PPAR-alpha agonist.

Target	Actions	Organism
APeroxisome proliferator-activated receptor gamma	activator	Humans

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Absorption

In rat studies, the AUC for the doses 0.5, 1, and 2 mg/kg, AUC values were determined to be 459, 514, and 481 ug min/mL respectively. Absoprtion occurs rapidly after administration, with Tmax of 67.5 and 48.8 min and a Cmax of 0.962 and 0.4.94 ug/mL following doses of 0.5 and 2 mg/kg, respectively. Absolute bioavailability after oral administration was nearly complete and apparently not affected by the dosage; 92.1% following a 0.5 mg/kg dose and 99.0% following a 2 mg/kg dose. Furthermore, the extent of LB remaining in the GI tract at 24 h was found to be negligible, with values less than 0.2% of the oral dose, suggesting that the intestinal absorption is complete in rats at the dose range studied ².

Volume of distribution

The steady state volume of distribution (Vss) of lobeglitazone was found to be 189–276 mL/kg. Vss was not found to vary statistically with the dose, suggesting that lobeglitazone follows linear kinetics ².

Protein binding

Lobeglitazone was found to bind extensively to plasma proteins (i.e., up to 99.9%) with no appreciable concentration dependency on the unbound fraction ².

Metabolism

Rat studies with lobeglitazone have suggested that it is primarily metabolized by cytochrome P450 (CYP) isozymes ², however the exact enzymes involved in its metabolism have yet to be elucidated. The structure of Lobeglitazone's five major metabolites have been characterized along with their pharmacokinetic parameters, and can be seen in the metabolism section below. In rat studies, demethylation and hydroxylation appear to be the primary metabolic pathways. The most abundant metabolite found in these studies was confirmed in vivo as M1, a demethylated derivative of lobeglitazone; its rate of formation was found to be approximately 0.216 ∼ 0.252 mL/min/kg, representing approximately 9.76% of the total lobeglitazone elimination in vivo in rats ⁵.

• Lobeglitazone
  M1
• Lobeglitazone
  M2

Route of elimination

It has been reported that the combined extent of the excretion of lobeglitazone to the bile, urine and intestine is low (less than 10% of total dose), suggesting that the major route of elimination for the drug involves its metabolism ².

Half life

Following an intravenous dosage of 1 mg/kg, the half life was found to be 110 min ².

Clearance

In rat studies, systemic clearance was found to be between 1.95 and 2.19 mL/min/kg regardless of dosage ².

Toxicity

Lobeglitazone showed a similar adverse effect profile to pioglitazone, another thiazolidinedione medication from the same class. The most concerning side effects found were edema and weight gain, with no severe adverse effects. Notably, there were no observable changes to patients with heart failure, which is a concern associated with other medications of the same class ³.

Affected organisms

Not Available

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

• All Drugs
• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental

Drug	Interaction
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(R)-warfarin	The metabolism of (R)-warfarin can be decreased when combined with Lobeglitazone.
(S)-Warfarin	The metabolism of (S)-Warfarin can be decreased when combined with Lobeglitazone.
2,4-thiazolidinedione	The risk or severity of hypoglycemia can be increased when Lobeglitazone is combined with 2,4-thiazolidinedione.
3,5-diiodothyropropionic acid	The metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Lobeglitazone.
4-hydroxycoumarin	The metabolism of 4-hydroxycoumarin can be decreased when combined with Lobeglitazone.
5-(2-methylpiperazine-1-sulfonyl)isoquinoline	The therapeutic efficacy of Lobeglitazone can be increased when used in combination with 5-(2-methylpiperazine-1-sulfonyl)isoquinoline.
5-androstenedione	The metabolism of Lobeglitazone can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide B	The metabolism of Lobeglitazone can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanine	The metabolism of 6-O-benzylguanine can be decreased when combined with Lobeglitazone.
7-ethyl-10-hydroxycamptothecin	The metabolism of Lobeglitazone can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.

Additional Data Available

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Severity
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Food Interactions

Not Available

References

Synthesis Reference

Kim BY, Ahn JB, Lee HW, Kang SK, Lee JH, Shin JS, Ahn SK, Hong CI, Yoon SS: Synthesis and biological activity of novel substituted pyridines and purines containing 2,4-thiazolidinedione. Eur J Med Chem. 2004 May;39(5):433-47.

General References

1. Lee YH, Kim JH, Kim SR, Jin HY, Rhee EJ, Cho YM, Lee BW: Lobeglitazone, a Novel Thiazolidinedione, Improves Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness. J Korean Med Sci. 2017 Jan;32(1):60-69. doi: 10.3346/jkms.2017.32.1.60. [PubMed:27914133]
2. Lee JH, Noh CK, Yim CS, Jeong YS, Ahn SH, Lee W, Kim DD, Chung SJ: Kinetics of the Absorption, Distribution, Metabolism, and Excretion of Lobeglitazone, a Novel Activator of Peroxisome Proliferator-Activated Receptor Gamma in Rats. J Pharm Sci. 2015 Sep;104(9):3049-59. doi: 10.1002/jps.24378. Epub 2015 Feb 3. [PubMed:25648999]
3. Jin SM, Park CY, Cho YM, Ku BJ, Ahn CW, Cha BS, Min KW, Sung YA, Baik SH, Lee KW, Yoon KH, Lee MK, Park SW: Lobeglitazone and pioglitazone as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, parallel-group, active-controlled, phase III clinical trial with a 28-week extension. Diabetes Obes Metab. 2015 Jun;17(6):599-602. doi: 10.1111/dom.12435. Epub 2015 Feb 8. [PubMed:25580775]
4. Kim BY, Ahn JB, Lee HW, Kang SK, Lee JH, Shin JS, Ahn SK, Hong CI, Yoon SS: Synthesis and biological activity of novel substituted pyridines and purines containing 2,4-thiazolidinedione. Eur J Med Chem. 2004 May;39(5):433-47. [PubMed:15110969]
5. Lee JH, Ahn SH, Maeng HJ, Lee W, Kim DD, Chung SJ: The identification of lobeglitazone metabolites in rat liver microsomes and the kinetics of the in vivo formation of the major metabolite M1 in rats. J Pharm Biomed Anal. 2015 Nov 10;115:375-82. doi: 10.1016/j.jpba.2015.07.040. Epub 2015 Jul 30. [PubMed:26275726]

External Links

PubChem Compound

9826451

PubChem Substance

310265106

ChemSpider

8002194

ChEBI

136052

ChEMBL

CHEMBL3585580

Wikipedia

Lobeglitazone

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Completed	Not Available	Healthy Male Volunteers	1
1	Completed	Not Available	Healthy Volunteers	1
1	Completed	Not Available	Liver Dysfunction	1
1	Completed	Treatment	Healthy Volunteers / Impaired Renal Function	1
1	Completed	Treatment	Type 2 Diabetes Mellitus	6
1	Not Yet Recruiting	Treatment	Type 2 Diabetes Mellitus	1
2	Completed	Treatment	Type 2 Diabetes Mellitus	1
3	Completed	Treatment	Type 2 Diabetes Mellitus	2
3	Recruiting	Treatment	Type2 Diabetes	3
4	Completed	Treatment	Non-Alcoholic Fatty Liver Disease (NAFLD) / Type 2 Diabetes Mellitus	1
4	Not Yet Recruiting	Treatment	Inadequate Glucose Control / Type 2 Diabetes Mellitus	1
4	Recruiting	Treatment	Type 2 Diabetes Mellitus	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

Not Available

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0181 mg/mL	ALOGPS
logP	3.84	ALOGPS
logP	4.31	ChemAxon
logS	-4.4	ALOGPS
pKa (Strongest Acidic)	7.61	ChemAxon
pKa (Strongest Basic)	3.96	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	7	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	102.88 Å2	ChemAxon
Rotatable Bond Count	10	ChemAxon
Refractivity	129.63 m3·mol-1	ChemAxon
Polarizability	49.64 Å3	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Taxonomy

Description

This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.

Kingdom

Organic compounds

Super Class

Organic oxygen compounds

Class

Organooxygen compounds

Sub Class

Ethers

Direct Parent

Diarylethers

Alternative Parents

Phenoxy compounds / Methoxybenzenes / Anisoles / Dialkylarylamines / Thiazolidinediones / Alkyl aryl ethers / Aminopyrimidines and derivatives / Imidolactams / Heteroaromatic compounds / DicarboximidesThiocarbamic acid derivatives / Organic carbonic acids and derivatives / Azacyclic compounds / Carbonyl compounds / Hydrocarbon derivatives / Organic oxides / Organopnictogen compounds

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Substituents

Diaryl ether / Phenoxy compound / Anisole / Phenol ether / Methoxybenzene / Dialkylarylamine / Alkyl aryl ether / Aminopyrimidine / Thiazolidinedione / Monocyclic benzene moietyPyrimidine / Imidolactam / Benzenoid / Heteroaromatic compound / Dicarboximide / Thiazolidine / Carbonic acid derivative / Thiocarbamic acid derivative / Azacycle / Carboxylic acid derivative / Organoheterocyclic compound / Organonitrogen compound / Organopnictogen compound / Organic nitrogen compound / Carbonyl group / Hydrocarbon derivative / Organic oxide / Aromatic heteromonocyclic compound

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Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

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Drug created on October 16, 2015 16:12 / Updated on May 01, 2019 13:30