Lobeglitazone Sulfate

Lobeglitazone sulfate, an oral peroxisome proliferator-activated receptor (PPARa/c) dual agonist with IC50 = 20 and 18 nM respectively, was developed by Chong Kun Dang Pharmaceutical in Korea for the treatment of diabetes. This drug is differentiated from two other PPAR agonists available—pioglitazone and rosiglitazone —which lack PPARa activity. The most likely processscale preparation of lobeglitazone sulfate follows the route described in a process communication from Chong Kun Dang Pharmaceutical.

Lobeglitazone sulfate is a new type of thiazolidinedione. Lobeglitazone sulfate is the orally active agonist for PPAR with EC50 of 137.4 nM and 546.3 nM for PPARγ and PPARα. Lobeglitazone sulfate is the inhibitor for ERK/JNK/Smad/NF-κB signaling pathway. Lobeglitazone sulfate exhibits anti-inflammatory, anti-diabetic, anti-fibrotic and anti-atherosclerotic properties[1][2][3][4][5][6].

Commercially available 4,6-dichloropyrimidine (152) was treated with a stoichiometric equivalent of p-methoxyphenol (153) in the presence of KF in warm DMF . Upon completion of this reaction, 2-methylaminoethanol was added to the mixture to provide pyrimidine 154 in high yield. Next, alcohol 154 underwent a substitution reaction with p-fluorobenzaldehyde (155) under basic conditions to provide alkoxy benzaldehyde 156 which was converted to the benzylidene thiazolidindione 158 upon subjection to Knoevenagel conditions with 2,4-thiazolidinedione (157) in 90% yield. Finally, reduction of olefin 158 was facilitated by treatment with the Hantzsch ester (159) in the presence of silica gel followed by treatment with methanolic sulfuric acid (96%) at low temperature to ultimately furnish lobeglitazone sulfate in 90% yield.

PPARγ: 137.4 nM (EC₅₀); PPARα: 546.3 nM (EC₅₀)

[1] Bae J, et al. Lobeglitazone: A Novel Thiazolidinedione for the Management of Type 2 Diabetes Mellitus. Diabetes Metab J. 2021 May;45(3):326-336.
[2] Jeong D, et al., Lobeglitazone Exerts Anti-Inflammatory Effect in Lipopolysaccharide-Induced Bone-Marrow Derived Macrophages. Biomedicines. 2021 Oct 10;9(10):1432. DOI:10.3390/biomedicines9101432
[3] Nuwormegbe S, et al. Lobeglitazone attenuates fibrosis in corneal fibroblasts by interrupting TGF-beta-mediated Smad signaling. Graefes Arch Clin Exp Ophthalmol. 2022 Jan;260(1):149-162. DOI:10.1007/s00417-021-05370-2
[4] Lim S, et al., Effect of a new PPAR-gamma agonist, lobeglitazone, on neointimal formation after balloon injury in rats and the development of atherosclerosis. Atherosclerosis. 2015 Nov;243(1):107-19. DOI:10.1016/j.atherosclerosis.2015.08.037