Description
Pioglitazone is an agonist of the peroxisome proliferator-activated receptor γ (PPARγ; EC
50 = ~500-600 nM for both human and murine PPARγ). It is selective for PPARγ over PPARα, exhibiting low level activation of PPARα at 1 μM and 5.4-fold activation at a concentration of 10 μM. Pioglitazone inhibits pyruvate oxidation and glucose production in hepatocytes when used at a concentration of 10 μM.
In vivo, pioglitazone (0.3-3 mg/kg per day) reduces hyperglycemia, hyperlipidemia, and hyperinsulinemia in a dose-dependent manner in male Wistar fatty rats. It reduces the number of lesions in a transgenic rat adenocarcinoma of prostate (TRAP) model. Pioglitazone (2.5 mg/kg) also decreases production of neuroinflammatory cytokines and reduces immobility in the forced swim and tail suspension tests in a mouse model of chronic mild stress, indicating antidepressant-like activity that can be reversed by the PPARγ antagonist GW9662 .
Chemical Properties
Colorless needle-like crystals from dimethylformamide-water, melting point 183-184°C. Pioglitazone Hydrochloride (Pioglitazone Hydrochloride): C19H20N2O3SHCl.[112529-15-4]. Colorless prismatic crystals from ethanol, melting point 193-194°C.
Originator
Actos ,Eli Lilly ,USA
Uses
antihyperlipidemic, HMGCoA reductase inhibitor
Uses
Pioglitazone shows antidiabetic activity in patients with type 2 diabetes mellitus.
Indications
Pioglitazone is approved for use as monotherapy
and in conjunction with metformin, sulfonylureas, and
insulin. It is taken once a day with or without food.
Though pioglitazone may also cause a small increase in
low-density lipoprotein concentrations, there is usually
a modest decrease in triglyceride levels, but it unclear
whether this has any clinical significance or persists in
the long term.
Definition
ChEBI: A member of the class of thiazolidenediones that is 1,3-thiazolidine-2,4-dione substituted by a benzyl group at position 5 which in turn is substituted by a 2-(5-ethylpyridin-2-yl)ethoxy group at position 4 of the phenyl ring. It exhibits hypoglycemic acti
ity.
Manufacturing Process
To a solution of 2-(5-ethyl-2-pyridyl)ethanol (53.0 g) and 4-fluoronitrobenzene (47.0 g) in DMF (500 ml) was added portionwise under ice-cooling 60% sodium hydride in oil (16.0 g). The mixture was stirred under ice-cooling for one hour, then at room temperature for 30 min, poured into water and extracted with ether. The ether layer was washed with water and dried (MgSO4). The solvent was evaporated off to give 4-[2-(5-ethyl-2pyridyl)ethoxy]nitrobenzene as crystals (62.0 g, 62.9%). Recrystallization from ether-hexane gave colorless prisms, melting point 53°-54°C.
A solution of 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene (60.0 g) in methanol (500 ml) was hydrogenated at room temperature under one atmospheric pressure in the presence of 10% Pd-C (50% wet, 6.0 g). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in acetone (500 ml)methanol (200 ml). To the solution was added a 47% HBr aqueous solution (152 g). The mixture was cooled, to which was added dropwise a solution of NaNO2 (17.3 g) in water (30 ml) at a temperature not higher than 5°C. The whole mixture was stirred at 5°C for 20 min, then methyl acrylate (112 g) was added thereto and the temperature was raised to 38°C. Cuprous oxide (2.0 g) was added to the mixture in small portions with vigorous stirring. The reaction mixture was stirred until nitrogen gas evolution ceased, and was concentrated under reduced pressure. The concentrate was made alkaline with concentrated aqueous ammonia, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4) The solvent was evaporated off to leave methyl 2-bromo-3-{4-[2-(5-ethyl-2pyridyl)ethoxy]phenyl}propionate as a crude oil (74.09 g, 85.7%).
A mixture of the crude oil of methyl 2-bromo-3-{4-[2-(5-ethyl-2pyridyl)ethoxy]phenyl}propionate (73.0 g) thiourea (14.2 g), sodium acetate (15.3 g) and ethanol (500 ml) was stirred for 3 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the concentrate was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, to which were added water (200 ml) and ether (100 ml). The whole mixture was stirred for 10 min to yield 5-{4-[2-(5-ethyl-2pyridyl)ethoxy]benzyl}-2-imino-4-thiazolidinone as crystals (0.3 g, 523.0%). Recrystallization from methanol gave colorless prisms, melting point 187°188°C, dec.
A solution of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2-imino-4thiazolidinone (23.5 g) in 2 N HCl (200 ml) was refluxed for 6 hours. The solvent was evaporated off under reduced pressure, and the residue was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The crystals (23.5 g, 97.5%) which precipitated were collected by filtrationand recrystallized from DMF-H2O to give 5-{4-[2-(5-ethyl-2pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione as colorless needles (20.5 g, 86.9%), melting point 183°-184°C.
In practice it is usually used as hydrochloride salt.
brand name
Actos (Takeda).
Therapeutic Function
Antidiabetic
General Description
Pioglitazone, (±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (Actos),is an odorless, white, crystalline powder that must be convertedto a salt such as its hydrochloride before it will haveany water solubility. Although the molecule contains one chiralcenter, the compound is used as the racemic mixture. Thisis primarily a result of the in vivo interconversion of the twoenantiomers. Thus, there are no differences in the pharmacologicalactivity of the two enantiomers.
References
[1] JUNICHI SAKAMOTO . Activation of Human Peroxisome Proliferator-Activated Receptor (PPAR) Subtypes by Pioglitazone[J]. Biochemical and biophysical research communications, 2000, 278 3: Pages 704-711. DOI:
10.1006/bbrc.2000.3868[2] CHRISTOPHER E. SHANNON. Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes[J]. The FEBS journal, 2016, 284 3: 451-465. DOI:
10.1111/febs.13992[3] Y SUGIYAMA. Effects of pioglitazone on glucose and lipid metabolism in Wistar fatty rats.[J]. Arzneimittel-Forschung-Drug Research, 1990, 40 3: 263-267.
[4] SHUGO SUZUKI. Pioglitazone, a Peroxisome Proliferator-Activated Receptor γ Agonist, Suppresses Rat Prostate Carcinogenesis[J]. International Journal of Molecular Sciences, 2016, 17 1. DOI:
10.3390/ijms17122071[5] QIUYING ZHAO. The antidepressant-like effects of pioglitazone in a chronic mild stress mouse model are associated with PPARγ-mediated alteration of microglial activation phenotypes[J]. Journal of Neuroinflammation, 2016, 47 1. DOI:
10.1186/s12974-016-0728-y
