Investigational Drug Details
| Drug ID: | D311 |
| Drug Name: | Rosiglitazone |
| Synonyms: | (±)-5-[p-[2-(methyl-2-pyridylamino)ethoxy]benzyl]-2,4-thiazolidinedione; (RS)-5-{4-[2-(Methyl-2-pyridylamino)ethoxy]benzyl}-2,4-thiazolidinedion; Rosiglitazone |
| Type: | Chemical drug |
| DrugBank ID: | DB00412 |
| DrugBank Description: | Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is marketed by the pharmaceutical company GlaxoSmithKline as a stand-alone drug (Avandia) and in combination with metformin (Avandamet) or with glimepiride (Avandaryl). Like other thiazolidinediones, the mechanism of action of rosiglitazone is by activation of the intracellular receptor class of the peroxisome proliferator-activated receptors (PPARs), specifically PPARγ. Rosiglitazone is a selective ligand of PPARγ, and has no PPARα-binding action. Apart from its effect on insulin resistance, it appears to have an anti-inflammatory effect: nuclear factor kappa-B (NFκB) levels fall and inhibitor (IκB) levels increase in patients on rosiglitazone. Recent research has suggested that rosiglitazone may also be of benefit to a subset of patients with Alzheimer's disease not expressing the ApoE4 allele. This is the subject of a clinical trial currently underway. |
| PubChem ID: | 77999 |
| CasNo: | 122320-73-4 |
| Repositioning for NAFLD: | Yes |
| SMILES: | CN(CCOC1CCC(CC2SC(=O)NC2=O)CC1)C1CCCCN1 |
| Structure: |
|
| InChiKey: | CZHAQHXDBPAXKQ-UHFFFAOYSA-N |
| Molecular Weight: | 357.435 |
| DrugBank Targets: | Peroxisome proliferator-activated receptor gamma agonist; Long-chain-fatty-acid--CoA ligase 4 inhibitor; Peroxisome proliferator-activated receptor alpha; Peroxisome proliferator-activated receptor delta; Retinoic acid receptor RXR-alpha; Retinoic acid re |
| DrugBank MoA: | Rosiglitazone acts as a highly selective and potent agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to insulin. |
| DrugBank Pharmacology: | When rosiglitazone is used as monotherapy, it is associated with increases in total cholesterol, LDL, and HDL. It is also associated with decreases in free fatty acids. Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over time. |
| DrugBank Indication: | Rosiglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. |
| Targets: | PPARG agonist; PPARA; PPARD |
| Therapeutic Category: | Improve insulin resistance |
| Clinical Trial Progress: | Phase 2 completed (NCT00492700: Rosiglitazone has a substantial antisteatogenic effect in the first year of treatment without additional benefit with longer therapy despite a maintained effect on insulin sensitivity and transaminase levels. This suggests that improving insulin sensitivity might not be sufficient in NASH and that additional targets of therapy for liver injury should be explored.) |
| Latest Progress: | Failed in clinical trials |
| Trial ID | Source ID | Phases | Status | Study Results | Start Date | Last Update Posted | |
|---|---|---|---|---|---|---|---|
| L0109 | NCT00252499 | Not applicable | Terminated | Has Results | October 2005 | August 20, 2014 | Details |
| L0125 | NCT00699036 | Phase 2 | Unknown status | No Results Available | April 2007 | June 19, 2009 | Details |
| L0251 | NCT00492700 | Phase 2 | Completed | No Results Available | January 2003 | June 27, 2007 | Details |
| L0327 | NCT01406704 | Phase 4 | Terminated | No Results Available | January 2004 | August 19, 2011 | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T03 | Peroxisome proliferator-activated receptor alpha | PPARA | agonist | Nuclear hormone receptor | Q07869 | PPARA_HUMAN | Details |
| T04 | Peroxisome proliferator-activated receptor delta | PPARD | agonist | Nuclear hormone receptor | Q03181 | PPARD_HUMAN | Details |
| T05 | Peroxisome proliferator-activated receptor gamma | PPARG | agonist | Nuclear hormone receptor | P37231 | PPARG_HUMAN | Details |
| Strategy ID | Strategy | Synonyms | Related Targets | Related Drugs | |
|---|---|---|---|---|---|
| S08 | Lifestyle measures | Lifestyle intervention; weight loss; diet adaptation; dietary interventions; lifestyle modifications; Exercise | -- | -- | Details |
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Article ID | PMID | Source | Title | |
|---|---|---|---|---|
| A00656 | 35013417 | Sci Rep | Different sites of actions make different responses to thiazolidinediones between mouse and rat models of fatty liver. | Details |
| A02326 | 34417811 | Endocrinology | Rosiglitazone Requires Hepatocyte PPARγ Expression to Promote Steatosis in Male Mice With Diet-Induced Obesity. | Details |
| A02440 | 34371198 | Prostaglandins Other Lipid Mediat | Lipocalin-type Prostaglandin D2 Synthase appears to function as a Novel Adipokine Preventing Adipose Dysfunction in response to a High Fat Diet. | Details |
| A04933 | 33444819 | Cell Mol Gastroenterol Hepatol | Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver. | Details |
| A05528 | 33218077 | Int J Mol Sci | PNPLA3 I148M Up-Regulates Hedgehog and Yap Signaling in Human Hepatic Stellate Cells. | Details |
| A05612 | 33188625 | J Physiol Biochem | Regulation of peroxisome proliferator-activated receptor-gamma activity affects the hepatic stellate cell activation and the progression of NASH via TGF-β1/Smad signaling pathway. | Details |
| A06984 | 32673798 | Mol Metab | Non-alcoholic fatty liver disease and steatohepatitis: State of the art on effective therapeutics based on the gold standard method for diagnosis. | Details |
| A07125 | 32613381 | Cell Biol Toxicol | Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists. | Details |
| A07170 | 32593899 | Environ Res | Ferroptosis mediated by the interaction between Mfn2 and IREα promotes arsenic-induced nonalcoholic steatohepatitis. | Details |
| A07793 | 32353385 | Toxicol Appl Pharmacol | Metabolomic-based assessment reveals dysregulation of lipid profiles in human liver cells exposed to environmental obesogens. | Details |
| A08393 | 32128893 | J Gastroenterol Hepatol | Regulation of lipid-induced macrophage polarization through modulating peroxisome proliferator-activated receptor-gamma activity affects hepatic lipid metabolism via a Toll-like receptor 4/NF-κB signaling pathway. | Details |
| A08883 | 31953228 | Biochim Biophys Acta Mol Cell Biol Lipids | Effects of peptidoglycan on the development of steatohepatitis. | Details |
| A09343 | 31783920 | Syst Rev | Diabetes drugs for nonalcoholic fatty liver disease: a systematic review. | Details |
| A09662 | 31654717 | Cell Signal | Identification of Nogo-B as a new molecular target of peroxisome proliferator-activated receptor gamma. | Details |
| A10514 | 31307592 | Adv Pharmacol | Drug-induced liver injury in obesity and nonalcoholic fatty liver disease. | Details |
| A11743 | 30769284 | Redox Biol | Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis. | Details |
| A12923 | 30225267 | J Diabetes Res | Rosiglitazone Elicits an Adiponectin-Mediated Insulin-Sensitizing Action at the Adipose Tissue-Liver Axis in Otsuka Long-Evans Tokushima Fatty Rats. | Details |
| A13037 | 30171034 | Dis Model Mech | Idebenone and coenzyme Q10 are novel PPARα/γ ligands, with potential for treatment of fatty liver diseases. | Details |
| A13079 | 30145577 | Ann Hepatol | Salidroside and Curcumin Formula Prevents Liver Injury in Nonalcoholic Fatty Liver Disease in Rats. | Details |
| A13453 | 29964161 | Pharmacol Res | Human-based systems: Mechanistic NASH modelling just around the corner? | Details |