Design and synthesis of alkoxyindolyl-3-acetic acid analogs as peroxisome proliferator-activated receptor-γ/δ agonists

Current Advances in the Biochemical and Physiological Aspects of the Treatment of Type 2 Diabetes Mellitus with Thiazolidinediones

“…However, despite their excellent potencies, the incidence of undesirable side effects has been linked to the use of TZDs, such as fluid retention, weight gain, hepatotoxicity (only for troglitazone), plasma-volume expansion, hemodilution, edema, and congestive heart failure; it is unknown if the toxicity is mediated by the activation of PPAR γ or if it is due to some other mechanism unique to the TZD drug, since neither rosiglitazone nor pioglitazone has displayed the increased incidence of hepatic adverse events seen with troglitazone, suggesting that hepatotoxicity may not be a class effect of PPAR γ agonists [ 6 , 7 , 29 – 32 ]; it has been proposed that the fluid adverse effects may be due to the regulation of PPAR γ through an unknown mechanism involved in the enhancement of urinary vasopressin excretion response [ 33 – 35 ].…”

“…The PPAR γ LBD contains a large binding pocket that allows a wide range of ligands searching for their proper conformations in order to form ligand-receptor complexes. Natural ligands of PPAR γ are fatty acids, while synthetic ligands can be classified as either full or partial agonists, such as TZDs, L-tyrosine analogs, and some nonsteroidal anti-inflammatory drugs [ 7 , 8 , 12 , 30 , 31 , 39 , 44 , 48 – 50 ]. The structure of the LBD is comprised of 13 helices and 4 β sheets, with a total volume of approximately 1300 to 1400 Å.…”

“…Binding of these ligands results in conformational changes of the receptors that facilitate their interaction with coactivator proteins. The resulting complexes activate the transcription of specific target genes, resulting in the induction of signaling cascades that mediate the physiological effects of the ligands ( Figure 4 ) [ 7 – 10 , 12 , 29 – 31 , 39 , 43 , 44 , 47 – 52 ].…”

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

“…They were attractive targets for diabetes, dyslipidemia, obesity, inflammation and atherosclerosis [3]. These identified subtypes displayed high similarity in sequence and significant specificity in physiological functions and tissue distribution.…”

“…These identified subtypes displayed high similarity in sequence and significant specificity in physiological functions and tissue distribution. PPARα is highly expressed in liver, kidney, heart, skeletal muscle and adipose tissue [4]. When activated by ligands, fatty acid oxidation and lipoprotein metabolism would be improved.…”