Balaglitazone

Balaglitazone is a partial agonist of peroxisome proliferator-activated receptor (PPAR) γ [1].
PPAR plays important roles in the regulation of insulin, triglycerides and lipid metabolism. It is an attractive target for the therapy of Type II Diabetes. Balaglitazone is a partial agonist of PPARγ. The maximum inhibition of PPARγ activity by balaglitazone is 52%. Thus balaglitazone is supposed to have decreased side effects. It has showed potent effects on lowering blood glucose in various animal models [1 and 2].
In a cell-based assay using HEK293 cells transfected with fused PPARγ, treatment of balaglitazone showed sigmoid activation with an EC50 value of 1.35μM. When combined with rosiglitazone, balaglitazone at increased concentrations resulted in the reduction of rosiglitazone’s activity to the level of balaglitazone alone at concentration of 100 nM [3].
In adult male diabetic mice, the oral administration of balaglitazone at increased doses showed more potent and efficacious at lowering glucose levels than rosiglitazone. Balaglitazone also caused reduction of bodyfluid accumulation andfat accumulation without heart enlargement, indicating that it had a better safety profile on the cardiovascular system. Besides that, balaglitazone treatment lasted for 21 days exerted no significant impact on the volumes of blood or plasma. Moreover, balaglitazone was found to have no effect on bone formation at concentrations of up to 10 mg/kg indicating that it was only a partial agonist and led no loss of bone [1 and 2].
References:
[1] Agrawal R, Jain P, Dikshit SN. Balaglitazone: a second generation peroxisome proliferator-activated receptor (PPAR) gamma (γ) agonist. Mini Rev Med Chem. 2012 Feb;12(2):87-97.
[2] Henriksen K, Byrjalsen I, Nielsen RH, Madsen AN, Larsen LK, Christiansen C, Beck-Nielsen H, Karsdal MA. A comparison of glycemic control, water retention, and musculoskeletal effects of balaglitazone and pioglitazone in diet-induced obese rats. Eur J Pharmacol. 2009 Aug 15;616(1-3):340-5.
[3] Larsen PJ, Lykkegaard K, Larsen LK, Fleckner J, Sauerberg P, Wassermann K, Wulff EM. Dissociation of antihyperglycaemic and adverse effects of partial perioxisome proliferator-activated receptor (PPAR-gamma) agonist balaglitazone. Eur J Pharmacol. 2008 Oct 31;596(1-3):173-9.

Efficacy and safety of the PPARgamma partial agonist balaglitazone compared with pioglitazone and placebo: a phase III, randomized, parallel-group study in patients with type 2 diabetes on stable insulin therapy.[Pubmed:21328517]

Diabetes Metab Res Rev. 2011 May;27(4):392-401.

BACKGROUND: Treatment of patients with perioxisome proliferator-activated receptor-gamma full agonists are associated with weight gain, heart failure, peripheral oedema, and bone loss. However, the safety of partial perioxisome proliferator-activated receptor-gamma agonists has not been established in a clinical trial. The Balaglitazone glucose Lowering Efficacy Trial aimed to establish the glucose-lowering effects and safety parameters of the perioxisome proliferator-activated receptor-gamma partial agonist Balaglitazone in diabetic patients on stable insulin therapy. METHODS: Four hundred and nine subjects from three countries with type 2 diabetes on stable insulin therapy were randomized to 26 weeks of double-blind treatment with once daily doses of 10 or 20 mg Balaglitazone, 45 mg pioglitazone, or matching placebo (n >/= 99 in each group). The primary endpoint was the efficacy of Balaglitazone 10 and 20 mg versus placebo on the absolute change in haemoglobin A(1c) . Secondary endpoints included levels of fasting serum glucose, and changes in body composition and bone mineral density as measured by dual energy X-ray absorptiometry, in comparison to pioglitazone 45 mg. This study is registered with Clinicaltrials.gov identifier: NCT00515632. RESULTS: In the 10- and 20-mg Balaglitazone groups, and in the 45-mg pioglitazone group, significant reductions in haemoglobin A(1c) levels were observed (-0.99, -1.11, and -1.22%, respectively; p < 0.0001) versus placebo. Fasting serum glucose was similarly reduced in all treatment arms. Dual energy X-ray absorptiometry analyses showed that, while Balaglitazone at 10 mg caused weight gain and fluid retention compared to placebo, the magnitude of these effects was significantly smaller than that of pioglitazone 45 mg and Balaglitazone 20mg. Balaglitazone at either dose did not appear to reduce bone mineral density, while Pioglitazone showed a trend towards a reduction. CONCLUSION: Patients treated with Balaglitazone at 10 mg and 20 mg and pioglitazone at 45 mg showed clinically meaningful improvements in glucose levels and HbA(1c) . With the 10 mg dose, the benefits (glucose & HgA(1c) lowering) and untoward effects (fluid and fat accumulation) were less, results that encourage further studies of this drug candidate.

Balaglitazone: a second generation peroxisome proliferator-activated receptor (PPAR) gamma (gamma) agonist.[Pubmed:22372600]

Mini Rev Med Chem. 2012 Feb;12(2):87-97.

Balaglitazone (DRF-2593) is a novel partial agonist of PPAR-gamma (gamma), which is developed by Dr. Reddy's 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-gamma modulators bind in distinct manners to the ligand-binding pocket of PPAR-gamma, 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 placebo and 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 10 mg and 20 mg show the similar magnitudes of the effects which comparable to the effects seen in the pioglitazone 45 mg group. The incidence of fluid retention and fat accumulation fewer than those observed with pioglitazone 45 mg. 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.

Dissociation of antihyperglycaemic and adverse effects of partial perioxisome proliferator-activated receptor (PPAR-gamma) agonist balaglitazone.[Pubmed:18761337]

Eur J Pharmacol. 2008 Oct 31;596(1-3):173-9.

Balaglitazone is a novel thiazolidinedione in clinical development for the treatment of type 2 diabetes. Common side effects associated with PPARgamma receptor agonists are weight gain, oedema and adipogenesis. Balaglitazone is a selective partial PPARgamma agonist and it has been speculated that such compounds have a more favourable safety margin than full agonists. We have compared impact of equi-efficacious antihyperglycaemic doses of Balaglitazone with full PPARgamma agonist rosiglitazone on body fluid accumulation, cardiac enlargement, and adipogenesis. Equi-efficacious antihyperglycaemic doses (ED(90)) of Balaglitazone (3 mg/kg/day) and rosiglitazone (6 mg/kg/day) were determined in male diabetic db/db mice. In adult male rats treated for up to 42 days, feeding, drinking, anthropometry, and plasma volumes were measured. Total plasma volume was measured with dye dilution technique. Compared to vehicle, rosiglitazone consistently increased food intake throughout the 42 day treatment period. In contrast, Balaglitazone increased food intake in the last week of the experiment. However, both rosiglitazone and Balaglitazone increased water intake. After 42 days, rosiglitazone treated rats displayed significantly elevated adiposity. Rosiglitazone increased total blood and plasma volumes throughout the treatment. Twenty-one days of Balaglitazone treatment had no significant impact on blood or plasma volumes, whilst 42 days of Balaglitazone increased plasma volume but to a significantly lesser extent than seen for rosiglitazone (vehicle: 46.1+/-1.5; Balaglitazone: 50.8+/-1.21; rosiglitazone: 54.6+/-1.6 ml/kg). Heart weight was significantly elevated only in rosiglitazone treated animals. At doses inducing comparable antihyperglycaemic control, the full PPARgamma agonist, rosiglitazone, induces more pronounced body fluid retention and heart enlargement than seen for the partial PPARgamma agonist, Balaglitazone. Thus, partial agonists may pose safer alternative to current anti-diabetic therapy with full PPARgamma agonist.