5-[(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}phenyl)methyl]-1,3-thiazolidine-2,4-dione

• ChemBase ID: 295
• Molecular Formular: C18H19N3O3S
• Molecular Mass: 357.42676
• Monoisotopic Mass: 357.11471248
• SMILES: S1C(Cc2ccc(OCCN(c3ncccc3)C)cc2)C(=O)NC1=O
• Canonical SMILES: O=C1NC(=O)C(S1)Cc1ccc(cc1)OCCN(c1ccccn1)C
• InChI: InChI=1S/C18H19N3O3S/c1-21(16-4-2-3-9-19-16)10-11-24-14-7-5-13(6-8-14)12-15-17(22)20-18(23)25-15/h2-9,15H,10-12H2,1H3,(H,20,22,23)
• InChIKey: YASAKCUCGLMORW-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 5-[(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}phenyl)methyl]-1,3-thiazolidine-2,4-dione
• IUPAC Traditional name: rosiglitazone
• Brand Name: Avandia; Rosiglizole
• Synonyms: Rosigliazone maleate; Rosiglitazone maleate; rosiglitazone; Rosiglitazone; Avandia; BRL-49653; 5-[[4-[2-(Methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione; Rosiglitazone; 5-(4-(2-(Methyl(pyridin-2-yl)amino)ethoxy)benzyl)thiazolidine-2,4-dione

Database IDs

• CAS Number: 122320-73-4
• MDL Number: MFCD00871760
• PubChem SID: 46504556; 160963758
• PubChem CID: 77999

CALCULATED PROPERTIES

JChem

• Acid pKa: 6.844312
• H Acceptors: 5
• H Donor: 1
• LogD (pH = 5.5): 2.151827
• LogD (pH = 7.4): 2.2077625
• Log P: 2.446348
• Molar Refractivity: 97.7899 cm^3
• Polarizability: 37.403675 Å^3
• Polar Surface Area: 71.53 Å^2
• Rotatable Bonds: 7
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 2.95
• LOG S: -3.97
• Solubility (Water): 3.80e-02 g/l

PROPERTIES

Physical Property

• Solubility: DMSO: ≥10 mg/mL
• Apperance: powder
• Hydrophobicity(logP): 2.4

Safety Information

• Storage Condition: -20°C
• German water hazard class: 3
• Storage Temperature: 2-8°C

Pharmacology Properties

• Target: PPAR

Product Information

• Purity: ≥98% (HPLC); 95+%
• Salt Data: Free Base
• Linear Formula: C18H19N3O3S

DETAILS

DrugBank - DB00412

• Drug Groups: approved; investigational
• 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.
• Indication: For the treatment of Type II diabetes mellitus
• Pharmacology: Rosiglitazone, a member of the drug group known as the thiazolidinediones or "insulin sensitizers", is not chemically or functionally related to the alpha-glucosidase inhibitors, the biguanides, or the sulfonylureas. Rosiglitazone targets insulin resistance and, hence, is used alone or with metformine or sulfonylurea to improve glycemic control in patients with type 2 diabetes mellitus.
• Toxicity: Side effects include fluid retention, congestive heart failure (CHF), liver disease
• Affected Organisms: Humans and other mammals
• Biotransformation: Hepatic. Rosiglitazone is extensively metabolized in the liver to inactive metabolites via N-demethylation, hydroxylation, and conjugation with sulfate and glucuronic acid. In vitro data have shown that Cytochrome (CYP) P450 isoenzyme 2C8 (CYP2C8) and to a minor extent CYP2C9 are involved in the hepatic metabolism of rosiglitazone.
• Absorption: The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in C_max and a delay in T_max (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food.
• Half Life: 3-4 hours
• Protein Binding: 99.8% bound to plasma proteins, primarily albumin.
• Elimination: Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively.
• Distribution: * 6 L
• Clearance: * Oral cl=3.03 +/- 0.87 L/hr [1 mg Fasting]; * Oral cl=2.89 +/- 0.71 L/hr [2 mg Fasting]; * Oral cl=2.85 +/- 0.69 L/hr [8 mg Fasting]; * Oral cl=2.97 +/- 0.81 L/hr [8 mg Fed]; * 3.15 L/hr [Population mean]
• References: Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P: Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab. 2004 Jun;89(6):2728-35. [Pubmed] ; Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006 Dec 7;355(23):2427-43. Epub 2006 Dec 4. [Pubmed]
• External Links: Wikipedia; RxList; PDRhealth; Drugs.com

Selleck Chemicals - S2556

Research Area: Immunology
Biological Activity:
Rosiglitazone (Avandia) is a potent antihyperglycemic agent and a potent thiazolidinedione insulin sensitizer with IC50 of 12, 4 and 9 nM for rat, 3T3-L1 and human adipocytes, respectively. Rosiglitazone (Avandia) has recently been identified as a high-affinity ligand for PPARγ, a nuclear hormone receptor that is abundantly expressed in adipocytes and plays a central role as a regulator of terminal adipocyte differentiation. Rosiglitazone (Avandia) acts primarily by increasing insulin sensitivity. Rosiglitazone (Avandia) improves glycemic control while reducing circulating insulin levels. Rosiglitazone (Avandia) is a member of the thiazolidinedione class of drugs. They reduce glucose, fatty acid, and insulin blood concentrations. They work by binding to the peroxisome proliferator-activated receptors (PPARs). Thiazolidinediones enter the cell, bind to the nuclear receptors, and affect the expression of DNA. Rosiglitazone (Avandia, BRL-49653) also appears to have an anti-inflammatory effect in addition to its effect on insulin resistance. [1][2]

Sigma Aldrich - R2408

Biochem/physiol Actions
Rosiglitazone is a potent agonist for PPARγ with an EC50 of 43 nM for the human receptor. It is antidiabetic, working as an insulin sensitizer by binding to the PPARγ receptors in fat cells and making the cells more responsive to insulin.

REFERENCES

• Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P: Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab. 2004 Jun;89(6):2728-35. Pubmed
• Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006 Dec 7;355(23):2427-43. Epub 2006 Dec 4. Pubmed
• Young PW et al. J Pharmacol Exp Ther. 1998 Feb; 284(2):751-9.