Details of the Drug

General Information of Drug (ID: DMHY3IP)

• Drug Name: Lobeglitazone
• Synonyms: Lobeglitazone sulfate; CKD-501; Dual PPARalpha/delta (type 2 diabetes), Chong Kun Dang

Indication

Disease Entry	ICD 11	Status	REF
Type-2 diabetes	5A11	Approved	[1]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 480.5
  Topological Polar Surface Area (xlogp); 4.3
  Rotatable Bond Count (rotbonds); 10
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 9
• ADMET Property:
  Clearance: The sytemic clearance of drug is 1.95-2.19 mL/min/kg [2]
  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 themajor route of elimination for the drug involves its metabolism [2]
  Half-life: The concentration or amount of drug in body reduced by one-half in 110 minutes [2]
  Metabolism: The drug is metabolized via the cytochrome P450 (CYP) isozymes [2]
  Vd: The volume of distribution (Vd) of drug is 0.189-0.276 L/kg [2]
• Chemical Identifiers:
  Formula: C24H24N4O5S
  IUPAC Name: 5-[[4-[2-[[6-(4-methoxyphenoxy)pyrimidin-4-yl]-methylamino]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
  Canonical SMILES: CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC
  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)
  InChIKey: CHHXEZSCHQVSRE-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 9826451
  ChEBI ID: CHEBI:136052
  CAS Number: 607723-33-1
  DrugBank ID: DB09198
  TTD ID: D04BCB
  INTEDE ID: DR0966

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Peroxisome proliferator-activated receptor alpha (PPARA)	TTJ584C	PPARA_HUMAN	Agonist	[1]
Peroxisome proliferator-activated receptor gamma (PPAR-gamma)	TTZMAO3	PPARG_HUMAN	Agonist	[1]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[3]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Substrate	[4]

Molecular Expression Atlas of This Drug

• The Studied Disease: Type-2 diabetes
• ICD Disease Classification: 5A11

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Peroxisome proliferator-activated receptor gamma (PPAR-gamma)	DTT	PPARG	2.41E-01	-0.06	-0.25
Cytochrome P450 2C8 (CYP2C8)	DME	CYP2C8	1.82E-04	-1.35E-01	-5.84E-01
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	1.04E-02	6.29E-02	3.54E-01

References

• [1] Tolerability and pharmacokinetics of lobeglitazone, a novel peroxisome proliferator-activated receptor-gamma agonist, after a single oral administration in healthy female subjects. Clin Drug Investig. 2014 Jul;34(7):467-74.
• [2] 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.
• [3] Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on the pharmacokinetics and pharmacodynamics of warfarin. Drug Des Devel Ther. 2015 Mar 2;9:737-43.
• [4] Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone. Clin Pharmacol Ther. 2005 May;77(5):404-14.
• [5] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [6] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [7] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [8] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [9] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [10] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [11] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [12] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [13] 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.
• [14] Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
• [15] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [16] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [17] Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics. 2003 Sep;13(9):565-75.
• [18] Analysis of human cytochrome P450 2C8 substrate specificity using a substrate pharmacophore and site-directed mutants. Biochemistry. 2004 Dec 14;43(49):15379-92.
• [19] Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8.
• [20] PharmGKB summary: mycophenolic acid pathway. Pharmacogenet Genomics. 2014 Jan;24(1):73-9.
• [21] Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
• [22] Expression of peroxisome proliferator-activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists. Int J Cancer. 2003 May 1;104(5):597-602.
• [23] Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nat Med. 2002 Nov;8(11):1281-7.
• [24] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [25] Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem. 2000 Jun 2;275(22):16638-42.
• [26] Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with... Clin Ther. 2005 Aug;27(8):1181-95.
• [27] A randomized-controlled trial to investigate the effects of rivoglitazone, a novel PPAR gamma agonist on glucose-lipid control in type 2 diabetes. Diabetes Obes Metab. 2011 Sep;13(9):806-13.
• [28] Balaglitazone: a second generation peroxisome proliferator-activated receptor (PPAR) gamma () agonist.Mini Rev Med Chem.2012 Feb;12(2):87-97.
• [29] Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR alpha and gamma agonist in healthy subjects and patients with type 2 diabetes. J Clin Pharmacol. 2003 Nov;43(11):1244-56.
• [30] Bezafibrate at clinically relevant doses decreases serum/liver triglycerides via down-regulation of sterol regulatory element-binding protein-1c in... Mol Pharmacol. 2009 Apr;75(4):782-92.
• [31] Pemafibrate: First Global Approval. Drugs. 2017 Oct;77(16):1805-1810.
• [32] Determination of chiglitazar, a dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist, in human plasma by liquid chromatograph... Pharmazie. 2007 Nov;62(11):825-9.
• [33] Tesaglitazar, a dual PPAR-/ agonist, hamster carcinogenicity, investigative animal and clinical studies.Toxicol Pathol.2012;40(1):18-32.
• [34] Dual peroxisome proliferator-activated receptor / agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects.Diabetes Care.2013 Oct;36(10):2923-30.
• [35] Pharmacokinetics, safety, and tolerability of saroglitazar (ZYH1), a predominantly PPARalpha agonist with moderate PPARgamma agonist activity in healthy human subjects. Clin Drug Investig. 2013 Nov;33(11):809-16.