Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C20H24O7S |
| Molecular Weight | 408.465 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CCO[C@@H](CC1=CC=C(OCCC2=CC=C(OS(C)(=O)=O)C=C2)C=C1)C(O)=O
InChI
InChIKey=CXGTZJYQWSUFET-IBGZPJMESA-N
InChI=1S/C20H24O7S/c1-3-25-19(20(21)22)14-16-6-8-17(9-7-16)26-13-12-15-4-10-18(11-5-15)27-28(2,23)24/h4-11,19H,3,12-14H2,1-2H3,(H,21,22)/t19-/m0/s1
| Molecular Formula | C20H24O7S |
| Molecular Weight | 408.465 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Optical Activity | UNSPECIFIED |
DescriptionCurator's Comment: description was created based on several sources, including
http://www.docguide.com/astrazeneca-discontinues-development-galida-tesaglitazar
Curator's Comment: description was created based on several sources, including
http://www.docguide.com/astrazeneca-discontinues-development-galida-tesaglitazar
Tesaglitazar, a dihydro cinnamate derivative (AZ 242), is a dual agonist of PPARα and γ that demonstrates IC50 values of 1 and 0.2 µM, respectively. It has been investigated its potential to address disorders in glucose and lipid metabolism in patients with type 2 diabetes. The drug had completed several phase III clinical trials, however in May, 2006 AstraZeneca announced that it had discontinued further development. Following analysis and interpretation of recently obtained results from the first four of eight phase 3 clinical trials (GALLANT 6,7,8 and 9) and one phase 2 trial (ARMOR), which were reviewed in consultation with external experts, the company considers that the overall benefit/risk profile is unlikely to offer patients significant advantage over currently available therapy. Central to the decision is data showing elevations in serum creatinine and an associated decrease in glomerular filtration rate (GFR). The magnitude of the serum creatinine elevation was greater than anticipated based on earlier clinical studies. Such elevations reversed towards baseline upon stopping treatment with the drug and have not been associated with kidney toxicity.
Originator
Approval Year
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
0.65 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15319332/ |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
0.41 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16920896/ |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
|
0.5 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16920896/ |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
14.9 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15319332/ |
1 mg single, intravenous dose: 1 mg route of administration: Intravenous experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
14.5 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15319332/ |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
13.1 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16920896/ |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
|
13.2 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16920896/ |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
45 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15319332/ |
1 mg single, intravenous dose: 1 mg route of administration: Intravenous experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
46 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15319332/ |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
36.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16920896/ |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED |
|
37.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16920896/ |
1 mg single, oral dose: 1 mg route of administration: Oral experiment type: SINGLE co-administered: |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
Funbound
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
0.11% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15319332/ |
TESAGLITAZAR plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: |
Doses
| Dose | Population | Adverse events |
|---|---|---|
1 mg 1 times / day multiple, oral Highest studied dose Dose: 1 mg, 1 times / day Route: oral Route: multiple Dose: 1 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Disc. AE: Stomach pain, Nausea... AEs leading to discontinuation/dose reduction: Stomach pain (1.5%) Sources: Nausea (1.5%) |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Nausea | 1.5% Disc. AE |
1 mg 1 times / day multiple, oral Highest studied dose Dose: 1 mg, 1 times / day Route: oral Route: multiple Dose: 1 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
| Stomach pain | 1.5% Disc. AE |
1 mg 1 times / day multiple, oral Highest studied dose Dose: 1 mg, 1 times / day Route: oral Route: multiple Dose: 1 mg, 1 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells. | 2014-04-01 |
|
| Tesaglitazar, a dual PPAR-α/γ agonist, hamster carcinogenicity, investigative animal and clinical studies. | 2012 |
|
| Comparative gene expression profiles induced by PPARγ and PPARα/γ agonists in rat hepatocytes. | 2011-07-01 |
|
| Proliferative and molecular effects of the dual PPARalpha/gamma agonist tesaglitazar in rat adipose tissues: relevance for induction of fibrosarcoma. | 2011-02 |
|
| Successful drug development despite adverse preclinical findings part 2: examples. | 2010-12 |
|
| A model for glucose, insulin, and beta-cell dynamics in subjects with insulin resistance and patients with type 2 diabetes. | 2010-08 |
|
| Gene Expression Changes Induced by PPAR Gamma Agonists in Animal and Human Liver. | 2010 |
|
| Peroxisome proliferator-activated receptor alpha and alpha/gamma agonists do not cause impairment in renal function in the rat. | 2010 |
|
| Tesaglitazar, a dual peroxisome proliferator-activated receptor agonist (PPAR alpha/gamma), improves metabolic abnormalities and reduces renal injury in obese Zucker rats. | 2010 |
|
| A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease. | 2009-07-20 |
|
| The dual PPARalpha/gamma agonist tesaglitazar blocks progression of pre-existing atherosclerosis in APOE*3Leiden.CETP transgenic mice. | 2009-04 |
|
| Design, synthesis, and biological evaluation of novel constrained meta-substituted phenyl propanoic acids as peroxisome proliferator-activated receptor alpha and gamma dual agonists. | 2008-10-23 |
|
| Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment. | 2008-08 |
|
| Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function--evidence of interconversion. | 2008-06 |
|
| Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, improves apolipoprotein levels in non-diabetic subjects with insulin resistance. | 2008-03 |
|
| PPARgamma in Kidney Physiology and Pathophysiology. | 2008 |
|
| Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARalpha + gamma Agonists. | 2008 |
|
| Mild electrical stimulation with heat shock ameliorates insulin resistance via enhanced insulin signaling. | 2008 |
|
| PPARgamma and Agonists against Cancer: Rational Design of Complementation Treatments. | 2008 |
|
| Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders. | 2008 |
|
| Should We Use PPAR Agonists to Reduce Cardiovascular Risk? | 2008 |
|
| PPAR Agonists and Cardiovascular Disease in Diabetes. | 2008 |
|
| Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, reduces atherosclerosis in female low density lipoprotein receptor deficient mice. | 2007-11 |
|
| Efficacy, safety and tolerability of tesaglitazar when added to the therapeutic regimen of poorly controlled insulin-treated patients with type 2 diabetes. | 2007-09 |
|
| The effects of tesaglitazar as add-on treatment to metformin in patients with poorly controlled type 2 diabetes. | 2007-09 |
|
| Tesaglitazar, as add-on therapy to sulphonylurea, dose-dependently improves glucose and lipid abnormalities in patients with type 2 diabetes. | 2007-09 |
|
| A double-blind, randomised trial of tesaglitazar versus pioglitazone in patients with type 2 diabetes mellitus. | 2007-09 |
|
| Improvement of postprandial lipid handling and glucose tolerance in a non-diabetic population by the dual PPARalpha/gamma agonist, tesaglitazar. | 2007-09 |
|
| Learning from tesaglitazar. | 2007-09 |
|
| The dual peroxisome proliferator-activated receptor alpha/gamma agonist tesaglitazar further improves the lipid profile in dyslipidemic subjects treated with atorvastatin. | 2007-09 |
|
| Peroxisome proliferator activated receptor alpha/gamma dual agonist tesaglitazar attenuates diabetic nephropathy in db/db mice. | 2007-08 |
|
| PPAR dual agonists: are they opening Pandora's Box? | 2007-08 |
|
| Quinoline-based derivatives of pirinixic acid as dual PPAR alpha/gamma agonists. | 2007-07 |
|
| Tesaglitazar, a PPARalpha/gamma agonist, induces interstitial mesenchymal cell DNA synthesis and fibrosarcomas in subcutaneous tissues in rats. | 2007-07 |
|
| Effect of tesaglitazar, a dual PPAR alpha/gamma agonist, on glucose and lipid abnormalities in patients with type 2 diabetes: a 12-week dose-ranging trial. | 2006-12 |
|
| Dual PPARalpha/gamma agonist tesaglitazar reduces atherosclerosis in insulin-resistant and hypercholesterolemic ApoE*3Leiden mice. | 2006-11 |
|
| Food does not affect the pharmacokinetics of tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist. | 2006-09 |
|
| Gateways to clinical trials. | 2006-05 |
|
| Therapeutic options in development for management of diabetes: pharmacologic agents and new technologies. | 2006-04-22 |
|
| Diabetes: assessing the pipeline. | 2006-04 |
|
| Tesaglitazar: a promising approach in type 2 diabetes. | 2006-03 |
|
| Tesaglitazar. | 2005-11 |
|
| Tesaglitazar, a dual PPAR{alpha}/{gamma} agonist, ameliorates glucose and lipid intolerance in obese Zucker rats. | 2005-10 |
|
| Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. | 2005-09-16 |
|
| Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. | 2005-09 |
|
| Pharmacokinetics and metabolism of tesaglitazar, a novel dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, after a single oral and intravenous dose in humans. | 2004-09 |
|
| Peroxisome proliferator-activated receptor (PPAR) activation induces tissue-specific effects on fatty acid uptake and metabolism in vivo--a study using the novel PPARalpha/gamma agonist tesaglitazar. | 2004-07 |
|
| Gateways to clinical trials. | 2003-11 |
|
| Gateways to clinical trials. | 2003-10 |
|
| Tesaglitazar AstraZeneca. | 2002-09 |
Sample Use Guides
concentration of drug was used: 0.1, 0.25, 0.5 and 1.0 mg/day
Route of Administration:
Oral
The effects of various PPAR agonists, i.e. fenofibrate, tesaglitazar etc on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists
| Substance Class |
Chemical
Created
by
admin
on
Edited
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| Record UNII |
6734037O3L
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| Record Status |
Validated (UNII)
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C98233
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TARGET -> AGONIST |
Tesaglitazar is a novel dual-acting peroxisome proliferator-activated receptor alpha and gamma agonist.
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TARGET -> AGONIST |
Tesaglitazar is a novel dual-acting peroxisome proliferator-activated receptor alpha and gamma agonist.
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ACTIVE MOIETY |
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| Biological Half-life | PHARMACOKINETIC |
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| Volume of Distribution | PHARMACOKINETIC |
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| Tmax | PHARMACOKINETIC |
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