Balaglitazone: A Second Generation Peroxisome Proliferator-Activated Receptor (PPAR) Gamma (γ) Agonist

R.      Agrawal; P.      Jain; S.      N. Dikshit

doi:10.2174/138955712798995048

Abstract

Balaglitazone (DRF-2593) is a novel partial agonist of PPAR-gamma (γ), which is developed by Dr. Reddys laboratories India. Balaglitazone is a second generation peroxisome proliferator-activated receptor (PPAR) gamma agonist with only partial agonistic properties. Balaglitazone is currently being evaluated in phase III clinical trial in United States and Europe. Selective PPAR-γ modulators bind in distinct manners to the ligand-binding pocket of PPAR-γ, leading to alternative receptor conformations, differential cofactor recruitment/displacement, differential gene expression, and ultimately differential biological responses. Based on this concept, new and improved novel antidiabetic agents are in current development. Clinical studies conducted with 409 subjects of randomized, double blind, parallel-group placeboand active comparator-controlled subject groups to determine the efficacy and safety of Balaglitazone. The study showed that the trial met its primary endpoint. Balaglitazone treated groups shown significantly reduce of HbA1c (%), FSG (mmol/L), postprandial glucose as comparison to pioglitazone. Phase III clinical studies data clearly shows that Balaglitazone provides robust glycemic control as an add-on to insulin therapy. Balaglitazone 10mg and 20mg show the similar magnitudes of the effects which comparable to the effects seen in the pioglitazone 45mg group. The incidence of fluid retention and fat accumulation fewer than those observed with pioglitazone 45mg. Hence, Balaglitazone is prominent candidate of new glitazone which requires fewer doses as comparison pioglitazone and shows better safety profile less incidence of special adverse effect like heart failure, peripheral oedema, and myocardial infarction. Unlike other marketed PPAR gamma agonists, Balaglitazone shows less fluid retention, less heart enlargement and no reduction of bone formation than full PPAR gamma agonists in preclinical studies. In present review, we have tried to cover classification PPARs various ligands, chemistry, physical properties, commercial synthesis, current patent status, polymorphic information, receptor interaction, pharmacophore rational, mechanism, adverse effect and clinical status of Balaglitazone, giving emphasis on medicinal chemistry aspect.

Keywords: Type 2 Diabetes, PPAR-γ, Selective PPARγ- modulators, PPARs, Balaglitazone, Thiazolidinediones, Novel Emerging Targets for Diabetes, Diabetes, Glitazone, agonists, yperinsulinemia, Polymorph, rosiglitazone