Saturday, June 25, 2016

Lobeglitazone I Dual PPAR Agonist I Treatment for T2DM | Treatment for Diabetes Mellitus

Lobeglitazone [5-(4-{2-[6-(4-Methoxyphenoxy)pyrimidin-4-yl]methylamino ethoxy}benzyl)thiazolidine-2,4-dione] is a an oral peroxisome proliferator-activated receptor; PPAR α/γ dual agonist with IC50 = 20 and 18 nM respectively used for the management of type 2 diabetes mellitus (DM). 

Lobeglitazone chemically belongs the TZD (thiazolidine-2,4-dione) class of drugs. It has been reported in the literature that PPARs are bound and activated by the TZD group and that this pharmacological activation enhances the action of insulin (insulin sensitizers) and promotes glucose utilization in peripheral tissues. This drug is differentiated from two other PPAR agonists available – Pioglitazone and Rosiglitazone – which lack PPARα activity.

Lobeglitazone: 2D and 3D Structure

Chong Kun Dang Pharmaceutical Corp., Korea, the principal discoverer of Lobeglitazone has credited the drug’s efficacy to its design, containing the TZD moiety with suitably placed substituted pyrimidines. These substituted pyrimidines were selected on their empirical effects on triglyceride accumulation in adipocytes in vitro and their glucose-lowering and lipid-modulating activities in diabetic mice in vivo
The efficacy of Lobeglitazone (0.5 mg/day) was not inferior to Pioglitazone (15 mg/day) as an add-on to Metformin in terms of the change in the HbA1c level from baseline. Additionally, the effects on lipid parameters, adiponectin secretion, and adverse effects (AEs) were similar to those observed with Pioglitazone. Moreover, unlike Pioglitazone, urinary excretion of Lobeglitazone is negligible in humans and no bladder cancer has been observed in two-year carcinogenicity studies in mice and rats.

Lobeglitazone Synthesis

Org Process Res Dev 2007, 11 (2), 190-199: It appears to be the industrial process.


1H NMR (Estimated) for Lobeglitazone

Experimental: 1H NMR (400 MHz, CDCl3) δ 3.12 (m, 4H), 3.45 (m, 1H), 3.83 (s, 3H), 4.00 (m, 2H), 4.16 (m, 2H), 4.50 (m, 1H), 5.84 (bs, 1H), 6.83 (m, 2H), 7.06 (m, 2H), 7.15 (m, 2H), 8.31 (s, 1H), 8.89 (bs, NH).

1. Jim, S. M.; et. al. 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, 17(6), 599-602. (FMO only)
2. Kim, J. W.; et. al. Tolerability and pharmacokinetics of lobeglitazone (CKD-501), a peroxisome proliferator-activated receptor-γ agonist: a single- and multiple-dose, double-blind, randomized control study in healthy male Korean subjects. Clin Ther 2011, 33(11), 1819-30. (FMO only) [gives a different structure for Lobeglitazone, appears to be a typos]
3. Lee, H. W.; et. al. Process Development and Scale-Up of PPAR α/γ Dual Agonist Lobeglitazone Sulfate (CKD-501). Org Process Res Dev 2007, 11(2), 190-199. (FMO only)