Synthesis and Antihyperglycemic Activity of Erythrose, Ribose and Substituted Pyrrolidine Containing Thiazolidinedione Derivatives

Abstract

Resistance to the metabolic actions of insulin is one of the salient features of impaired glucose tolerance and Type 2 diabetes mellitus (Type 2 DM). A number of prospective studies have shown that the development of insulin resistance is an early event in the natural progression of the disease.1,2) Thus, drugs that reverse the onset of insulin resistance fulfill a major medical need for the treatment of Type 2 DM.3) Insulin resistance is characterized by the impaired uptake and utilization of glucose in insulin-sensitive target organs such as adipocytes and skeletal muscle and by the impaired inhibition of hepatic glucose output. [4][5][6] Thiazolidinediones are a class of oral insulin-sensitizing agents that improve glucose utilization without stimulating insulin release. They significantly reduce glucose, lipid, and insulin levels in rodent models of Type 2 DM and obesity, [7][8][9] and recent clinical data support their efficacy in obese diabetic patients.10) The discovery of compounds which improve insulin resistance enables the continued treatment of Type 2 DM patients without inducing hypoglycemia. Clofibrate is the first such compound found to improve insulin resistance.11,12) It was followed by the discovery of thiazolidinedione compounds, typically represented by ciglitazone. [13][14][15] Of the thiazolidinedione compounds, ciglitazone (A), troglitazone (B), [16][17][18] englitazone (C), 19) pioglitazone (D), 20) and rosiglitazone (E) 21) are potential antidiabetic compounds that have been clinically examined.Scientists at Glaxo identified rosiglitazone as the first high-affinity ligand for peroxisome proliferator-activated receptor g (PPARg), a receptor subtype selectively expressed in adipocytes and shown to induce adipocyte differentiation. [22][23][24] These studies are predicting the thiazolidinedione compounds to be promising compounds, capable of ameliorating Type 2 DM by improving insulin resistance without inducing hypoglycemia. Troglitazone is the first of a novel class of compounds, the thiazolidinedione derivatives, to reach clinical practice. Troglitazone induces preadipocyte differentiation, probably via PPAR g receptors.25) While it is not clear whether the antihyperglycemic mechanism requires preadipocyte differentiation, the maximum glucose-lowering effect (about 40 mg/dl) of troglitazone is similar to that seen with metformin. Thiazolidinediones have been shown to improve insulin sensitivity/glucose utilization in animal model and to enhance insulin sensitivity in human. [26][27][28][29] But, it was assumed that troglitazone has the hepatotoxicity [30][31][32] due to the enterohepatic circulation of the metabolites, that is quinone moiety.In order to prevent this and to discover novel compounds which have the ability to increase glucose utilization, we focused our attention on the modification of chroman moiety to erythrose, ribose and substituted pyrrolidine group. As a result of our efforts, in this paper, we describe the synthesis and the in vitro glucose utilization activity. Sinc...

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

“…Lobeglitazone ( 1 ) (Figure ) which was reported in our previous works − belongs to the class of potent PPARα/γ dual agonists (PPARα EC 50 : 0.02 μM, PPARγ EC 50 : 0.018 μM, rosiglitazone; PPARα EC 50 : >10 μM, PPARγ EC 50 : 0.02 μM, pioglitazone PPARα EC 50 : >10 μM, PPARγ EC 50 : 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 .…”