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Lobeglitazone (trade name Duvie, Chong Kun Dang) is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonistfor both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.^[3]

Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie^® by Chong Kun Dang Corporation.

Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Duvie^® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.

Lobeglitazone which was reported in our previous works belongs to the class of potent PPARα/γ dual agonists (PPARα EC₅₀:  0.02 μM, PPARγ EC₅₀:  0.018 μM, rosiglitazone; PPARα EC₅₀:  >10 μM, PPARγ EC₅₀:  0.02 μM, pioglitazone PPARα EC₅₀:  >10 μM, PPARγ EC₅₀:  0.30 μM). Lobeglitazone has excellent pharmacokinetic properties and was shown to have more efficacious in vivo effects in KKA^y mice than rosiglitazone and pioglitazone.¹⁷ Due to its outstanding pharmacokinetic profile, lobeglitazone was chosen as a promising antidiabetes drug candidate.

Medical uses

Lobeglitazone is used to assist regulation of blood glucose level of diabetes mellitus type 2 patients. It can be used alone or in combination with metformin.^[4]

Lobeglitazone was approved by the Ministry of Food and Drug Safety (Korea) in 2013, and the postmarketing surveillance is on progress until 2019.^[4][5]

SYNTHESIS

PAPER

Org. Process Res. Dev. 2007, 11, 190-199.

Process Development and Scale-Up of PPAR α/γ Dual Agonist Lobeglitazone Sulfate (CKD-501)

http://pubs.acs.org/doi/abs/10.1021/op060087u

A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone (1), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (6), from the commercially available 4,6-dichloropyrimidine (3) without the isolation of pyrimidinyl phenoxy ether (4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione (10), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate (CKD-501, 2) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.

Silica gel TLC R_f = 0.35 (detection:  iodine char chamber, ninhydrin solution, developing solvents:  CH₂Cl₂/MeOH, 20:1); mp 111.4 °C; IR (KBr) ν 3437, 3037, 2937, 2775, 1751, 1698, 1648, 1610, 1503, 1439, 1301, 1246, 1215, 1183 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 3.09 (m, 4H), 3.29 (m, 1H), 3.76 (s, 3H), 3.97 (m, 2H), 4.14 (m, 2H), 4.86 (m, 1H), 6.06 (bs, 1H), 6.86 (m, 2H), 7.00 (m, 2H), 7.13 (m, 4H), 8.30 (s, 1H), 11.99 (s, NH); ¹³C NMR (100 MHz, CDCl₃) δ 37.1, 38.2, 53.7, 53.8, 56.3, 62.2, 65.8, 86.0, 115.1, 116.0, 123.0, 129.8, 131.2, 145.7, 153.4, 157.9, 158.1, 161.1, 166.5, 172.4, 172.5, 176.3, 176.5; MS (ESI)m/z (M + 1) 481.5; Anal. Calcd for C₂₄H₂₆N₄O₉S₂:  C, 49.82; H, 4.53; N, 9.68; S, 11.08. Found:  C, 49.85; H, 4.57; N, 9.75; S, 11.15.

PATENT

WO03080605A1.

References

Lobeglitazone

Systematic (IUPAC) name
5-[(4-[2-([6-(4-Methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidine-2,4-dione
Clinical data
Trade names	Duvie
Routes of administration	Oral
Legal status
Legal status	Rx-only in South Korea
Pharmacokinetic data
Protein binding	>99%[1]
Metabolism	liver (CYP2C9, 2C19, and 1A2)[1]
Biological half-life	7.8–9.8 hours[2]
Identifiers
CAS Number	607723-33-1
PubChem	CID 9826451
DrugBank	DB09198
ChemSpider	8002194
Synonyms	CKD-501
Chemical data
Formula	C24H24N4O5S
Molar mass	480.53616 g/mol
SMILES CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC

///Lobeglitazone Sulfate, CKD-501, Duvie^®,  Approved KOREA, Chong Kun Dang, A dual PPARα and PPARγ agonist , type 2 diabetes.

CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC.OS(=O)(=O)O

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