Description
Ciglitazone (74772-77-3) is a PPARγ agonist (EC50=3 μM). Stimulates adipogenesis in human mesenchymal stem cells. Ciglitazone inhibits HUVEC differentiation and angiogenesis. Cell permeable.
Chemical Properties
White Cyrstalline Solid
Originator
Ciglitazone, synthetized by Takeda and reported in 1982, was a result of screening of clofibrate analogues for
hypolipidemic activity.
Uses
Ciglitizone has been used as a proliferator-activated receptor γ (PPARγ) agonist:
- to study its effects on cell proliferation in human melanocytes
- to study its effects on pigmentation and migration of human melanocytes
It also may be used to study its effects on cell cycle and apoptosis in monocytic cells.
Uses
Displays antihyperglycemic activity in genetically obese mice. It is a selective PPARg agonist.
Definition
ChEBI: An aromatic ether that consists of 1,3-thiazolidine-2,4-dione with position 5 substituted by a 4-[(1-methylcyclohexyl)methoxy]benzyl group. A selective PPARgamma agonist.
General Description
A potent thiazolinedione (TDZ) type anti-hyperglycemic agent and a selective PPARγ agonist (EC
50 = 3 μM).
Biological Activity
Selective agonist at PPAR γ (peroxisome proliferator-activated receptor γ ). Activates PPAR γ with an EC 50 value of 3 μ M in vitro , and is at least 33-fold selective over PPAR α and δ . Antihyperglycemic in vivo .
Biochem/physiol Actions
Ciglitizone belongs to the class of thiazolidinediones and is a peroxisome proliferator-activated receptor γ (PPARγ) agonist. It exhibits anti-diabetic activity. Ciglitizone has the potential to treat tumor necrosis factor α (TNFα)-related apoptosis-inducing ligand (TRAIL)-refractory high-grade urothelial cancers.
Pharmacology
Ciglitazone reduced plasma triglycerides, hyperglycemia and hyperinsulinemia in several insulin resistant diabetic and nondiabetic rodent models after repeated oral dosing at doses of 100 – 300 mg/kg body weight, while having little or no effect in normal rodents or those with insulin deficient diabetes. In long-term animal studies lens cataracts occurred and ciglitazone development was discontinued.
Synthesis
Under the action of hexahydropyridine, p-hydroxybenzaldehyde and 2,4-thiazolidinedione condensed to form 5-[(4-hydroxyphenyl)methylidene]-2,4-thiazolidinedione, then reduced by palladium carbon catalyzed hydrogenation to form 5-[(4-hydroxyphenyl)methyl]-2,4-thiazolidinedione, and then reacted with potassium hydroxide to form the corresponding potassium salt, and then reacted with 5-ethyl-2-hydroxyethylpyridine and methanesulfonyl chloride to obtain the sulfonic acid ester of tyridazole, and finally acidified with hydrochloric acid to obtain its hydrochloride salt. Then it reacts with 5-ethyl-2-hydroxyethylpyridine and methylsulfonyl chloride to form tyridazole by reaction of sulfonate ester, and finally acidifies with hydrochloric acid to obtain its hydrochloride salt.
Mode of action
Ciglitizone is a thiazolidine-2,4-dione derivative. The mechanism of blood glucose lowering activity by thiazolidinedione derivatives has not been fully elucidated yet. Only minor or no effects are observed in normal animals or insulin sensitive diabetes models. In obese or hyperinsulinemic insulin resistant rodents thiazolidinediones lower insulin and triglyceride levels after treatment for 2 to 8 d. If hyperglycemia occurs, also the blood glucose concentration is reduced. Mechanistic in vitro studies with adipocytes have shown that the thiazolidinediones are ligands of the peroxisome proliferator activated receptor. Peroxisome proliferator activated receptors (PPARs) belong to the nuclear receptor superfamily of ligand-activated transcription factors. So far, three receptor subtypes have been identified: PPAR , PPAR , and PPAR . The PPARs are believed to play a physiological role in the regulation of lipid metabolism. The in vivo antihyperglycemic activity of thiazolidinediones strongly correlates with their potency as PPAR agonists in vitro.
References
[1] BARRIE C. C. CANTELLO. [[.omega.-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents[J]. Journal of Medicinal Chemistry, 1994, 37 23: 3977-3985. DOI:
10.1021/jm00049a017[2] X XIN. Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo.[J]. The Journal of Biological Chemistry, 1999, 274 13: 9116-9121. DOI:
10.1074/jbc.274.13.9116
