Hypoglycemic Activity of a Series of α-Alkylthio and α-Alkoxy Carboxylic Acids Related to Ciglitazone

Abstract

The thiazolidinedione moiety of ciglitazone and its analogues can be replaced by an alpha-alkoxy or alpha-thioether carboxylic acid group. The influence of the nature of the R group, the length of the connector to the aromatic backbone of the molecule, and the stereochemistry have been studied. The most potent compounds have glucose-lowering activity at doses as low as 0.01 mg/kg.

Studies on Non-Thiazolidinedione Antidiabetic Agents. 2. Novel Oxyiminoalkanoic Acid Derivatives as Potent Glucose and Lipid Lowering Agents.

“…[15][16][17] There are a number of groups that endeavor to produce new antidiabetic agents in this area. [18][19][20][21][22][23][24][25][26][27][28][29] Although the mechanisms of insulin resistance and action of 2,4-thiazolidinedione analogs and related compounds are not yet fully understood, a number of reports suggest that pioglitazone reduces insulin resistance. For example, treatment with pioglitazone increased the insulin action for the decrease of hepatic glucose production and for the increase of peripheral glucose utilization in Wistar fatty rats.…”

Studies on Non-Thiazolidinedione Antidiabetic Agents. 1. Discovery of Novel Oxyiminoacetic Acid Derivatives.

“…The analytical data of the synthesized oxyiminoacetic acids (7,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) are shown in Table 1.…”

“…Many companies are still endeavoring to find a new glucose lowering agent. [23][24][25][26][27][28][29][30][31][32][33][34][35] Although the precise mechanism of action of these drugs remains unknown, recent study suggests that antidiabetic thiazolidinediones interact with a family of nuclear receptors known as peroxisome proliferator-activated receptor (PPAR)-g. 36) PPARg is one of a subfamily of PPARs encoded by independent genes. Three human PPARs, designated PPARa, PPARg, and PPARd, have been identified to date.…”

“…There have been several reports of non-thiazolidine glucose and lipid lowering agents. [28][29][30][31]33) However, oxyiminoacetic acid derivatives as such agents have not been reported to our knowledge. For that reason, much effort was made to find more potent oxyiminoacetic acids.…”

Synthesis and Evaluation of 2-Nonylaminopyridine Derivatives as PPAR Ligands

“…1), which was designed based on the structure of rosiglitazone and 15d-PGJ 2 , 12,13) as a potent PPARg ligand. 14) To find more potent PPARg agonists and novel PPARa agonists, we chose compound 1 as the lead structure, because recent reports indicated that PPARg affinity can be increased by the introduction of substituents into the C-2 position of propanoic acid, [15][16][17][18][19] and minor structural modifications can convert PPAR subtype selectivity. [20][21][22] In this article, we report the synthesis, binding affinity and biological activity of PPAR ligands based on the structure of compound 1.…”