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Aleglitazar (RG-1439; RO-0728804; RG1439; RO0728804) is a novel and potent agonist of peroxisome proliferator-activated receptor (PPARα and PPARγ) with potential antidiabetic effects. In type 2 diabetics, aleglitazar, a PPAR modulator with strong affinity for PPARα and PPARγ, can help with insulin sensitivity, glucose regulation, and lipid levels. Phase III clinical trials are investigating it as a potential treatment for type II diabetes. Aleglitazar may have a therapeutic role in modifying cardiovascular risk factors and improving glycemic control in patients with type 2 diabetes, in addition to its positive effects on lipid and glucose parameters.
| Targets |
PPARγ (IC50 = 19 nM); PPARα (IC50 = 38 nM)
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| ln Vitro |
Aleglitazar demonstrates species selectivity towards PPARα, as evidenced by its EC50 values of 50 nM, 2.26 µM, and 2.34 µM for PPARα in humans, rat PPARα, and mouse PPARα, respectively[1].
Aleglitazar (0.01-40 µM; 12-48 hours) significantly increases lactate dehydrogenase (LDH) release at concentrations of 30 µM and 40 µM, but not at concentrations of 0.1 µM to 20 µM[2]. Aleglitazar (0.01–20 µM; 48 hr) reduces caspase-3 activity, cytochrome-C release, and apoptosis induced by hyperglycemia (HG, glucose 25 mM)[2]. Aleglitazar increases the viability of cells exposed to high blood sugar levels[2]. Aleglitazar attenuated hyperglycaemia-induced apoptosis, caspase-3 activity and cytochrome-C release and increased viability in human cardiomyocyte, cardiomyocytes from cardiac-specific peroxisome proliferator-activated receptor-γ knockout and wild-type mice. Hyperglycaemia reduced the antioxidant capacity and Aleglitazar significantly blunted this effect. Hyperglycaemia-induced reactive oxygen species production was attenuated by Aleglitazar in both human cardiomyocyte and wild-type mice cardiomyocytes. Aleglitazar improved cell viability in cells exposed to hyperglycaemia. The protective effect was partially blocked by short interfering RNA against peroxisome proliferator-activated receptor-α alone and short interfering RNA against peroxisome proliferator-activated receptor-γ alone and completely blocked by short interfering RNA to both peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ. Conclusion: Aleglitazar protects cardiomyocytes against hyperglycaemia-induced apoptosis by combined activation of both peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ in a short-term vitro model.[2] |
| ln Vivo |
Aleglitazar (0.3–3.0 mg/kg; intraperitoneal; daily; for 7 days) improves the anatomical and functional results of mild brain ischemia[3].
Aleglitazar inhibits the production of NO, the release of proinflammatory cytokines, migration, and phagocytosis, among other important aspects of microglia activation[3]. Aleglitazar reduces post-ischemic brain inflammatory responses[3]. |
| Enzyme Assay |
In this study, researchers incubated human cardiomyocytes, cardiomyocytes from cardiac-specific peroxisome proliferator-activated receptor-γ knockout or wild-type mice in normoglycaemic or hyperglycaemic conditions (glucose 25 mM). Cells were treated with different concentrations of Aleglitazar for 48 h. Researchers measured viability, apoptosis, caspase-3 activity, cytochrome-C release, total antioxidant capacity and reactive oxygen species formation in the treated cardiomyocytes. Human cardiomyocytes were transfected with short interfering RNA against peroxisome proliferator-activated receptor-α or peroxisome proliferator-activated receptor-γ[2].
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| Cell Assay |
Cell Line: human cardiomyocytes (HCM), wild-type mice cardiomyocytes (mCM-WT)
Concentration: 0.01 µM, 0.05 µM, 0.1 µM, 0.5 µM, 1 µM, 5 µM, 10 µM, 20 µM, 30 µM, 40 µM Incubation Time: 12 hours, 24 hours, 48 hours Result: Increased LDH release at concentrations of 30 µM and 40 µM. |
| Animal Protocol |
Male 129S6/SvEv mice (24-30 g), middle cerebral artery occlusion (MCAo) models[3]
0.3 mg/kg, 3.0 mg/kg Intraperitoneal injection, daily, for 7 days |
| References |
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| Additional Infomation |
Aleglitazar is an investigational drug from the company Hoffmann–La Roche and is currently in a phase III clinical trial called ALECARDIO. It is being investigated for use in patients with type II diabetes to reduce their risks of cardiovascular mortality and morbidity. Aleglitazar is an agonist at the peroxisome proliferator-activated receptor (PPAR) for both the PPARα and PPARγ receptor subtypes. In the phase II clinical trial called SYNCHRONY, with type II diabetic patients, aleglitazar was able to control both lipid and glucose levels in a synergistic manner while also having limited side effects and toxicity.
Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR) agonist, with hypoglycemic activity. Aleglitazar binds to both PPARalpha and PPARgamma and decreases plasma levels of glucose, LDL-C, triglycerides (TG) and increases HDL levels. This agent may be used for the treatment of diabetes and cardiovascular disease. Drug Indication Investigated for use in patients with type II diabetes to reduce their risks of cardiovascular mortality and morbidity. Mechanism of Action Aleglitazar was rationally designed to be an agonist at the peroxisome proliferator-activated receptor (PPAR) for both the PPARα and PPARγ receptor subtypes. Agonistic action at PPARα controls lipid levels, which improves dyslipidemia, and agonistic action at PPARγ controls glucose levels, which improves insulin sensitivity in diabetes. |
| Molecular Formula |
C24H23NO5S
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|---|---|
| Molecular Weight |
437.51
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| Exact Mass |
437.13
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| Elemental Analysis |
C, 65.89; H, 5.30; N, 3.20; O, 18.28; S, 7.33
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| CAS # |
475479-34-6
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| Related CAS # |
475479-34-6
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| PubChem CID |
10274777
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| Appearance |
White to yellow solid powder
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| Density |
1.29
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| Boiling Point |
665.151ºC at 760 mmHg
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| Flash Point |
356.071ºC
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| Index of Refraction |
1.627
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| LogP |
5.128
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
31
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| Complexity |
586
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C(CCOC2=CC=C(C[C@@H](C(O)=O)OC)C3=C2C=CS3)N=C(C4=CC=CC=C4)O1
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| InChi Key |
DAYKLWSKQJBGCS-NRFANRHFSA-N
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| InChi Code |
InChI=1S/C24H23NO5S/c1-15-19(25-23(30-15)16-6-4-3-5-7-16)10-12-29-20-9-8-17(14-21(28-2)24(26)27)22-18(20)11-13-31-22/h3-9,11,13,21H,10,12,14H2,1-2H3,(H,26,27)/t21-/m0/s1
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| Chemical Name |
(2S)-2-methoxy-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1-benzothiophen-7-yl]propanoic acid
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| Synonyms |
RG-1439; RO-0728804; RG1439; R 1439; Aleglitazar (USAN); Aleglitazar [USAN]; R1439; RO0728804; RO 0728804; RG 1439; R-1439; Aleglitazar
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ≥ 50 mg/mL (~114.3 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.71 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2857 mL | 11.4283 mL | 22.8566 mL | |
| 5 mM | 0.4571 mL | 2.2857 mL | 4.5713 mL | |
| 10 mM | 0.2286 mL | 1.1428 mL | 2.2857 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01197911 | Completed | Drug: aleglitazar | Healthy Volunteer | Hoffmann-La Roche | September 2010 | Phase 1 |
| NCT01701739 | Completed | Drug: aleglitazar Drug: digoxin |
Healthy Volunteer | Hoffmann-La Roche | October 2012 | Phase 1 |
| NCT01679639 | Completed | Drug: aleglitazar Drug: rifampicin |
Healthy Volunteer | Hoffmann-La Roche | August 2012 | Phase 1 |
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