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Rosiglitazone Maleate: Combating Insulin Resistance

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    Diabetes mellitus is a growing problem across the world. By the year 2010 it is estimated that over 221 million people will be afflicted with the disease1. Type 1 diabetes is the result of absolute insulin deficiency and is treated through the addition of exogenous insulin. Type 2 diabetes, non-insulin dependent diabetes (NIDDM), is characterized by a relative insulin deficiency and increased insulin resistance; it accounts for 90% of all cases of diabetes.

    Insulin resistance is the inability of cells to use insulin effectively which results in hyperglycemia even in the presence of adequate amounts of insulin. Insulin resistance contributes not only to diabetes, but to a plethora of other metabolic abnormalities including dyslipidemia, hypertension, and vasculopathy which are collectively termed the insulin resistance or cardiovascular dysmetabolic syndrome.2 Rosiglitazone, also known as Avandia, is effective only in the presence of insulin; its antihyperglycemic effect is the result of lowered insulin resistance in cells. Its development as a drug is described in this paper.

    Bioassay used to discover lead compound

    When GlaxoSmithKline started targeting insulin resistance in 1984 virtually nothing was known of the molecular mechanisms of insulin action, let alone what defects contribute to insulin resistance. Hence, in the absence of defined molecular targets, a mouse model of insulin resistant type II diabetes was used as a “catch-all” screen for insulin-sensitizing molecules.

    Antihyperglycemic activity was determined in genetically obese C57 B1/6 ob/ob mice which are insulin resistant, hyperinsulinemic, and glucose intolerant. The compound being screened was administered in the diet for 8 days (an 8 day repeat dose screen at 3 dosage levels), and antihyperglycemic efficacy was assessed using an oral glucose tolerance test. Potency of ~1mg/kg and oral activity were criteria for potential lead compounds.3

    Lead compounds discovered

    Clofibrate, a hypolipidaemic drug, was modified by Takeda and his commemorates to form ciglitazone. Ciglitazone was shown to be a very low potency (ED25 = 300�mol/kg) insulin sensitizer and was chosen as a lead compound for further studies.

    In dogs, rats, and men several metabolic oxidation products of the cyclohexane ring of ciglitazone are formed. One of these metabolites, AD 47431 was found to have more potent antihyperglycemic activity than ciglitazone in genetically obese and diabetic kk (kkAy) mice and was thus adopted as the new lead compound. The enhanced activity of AD 4743 may be related to ncreased bioavailability due to greater hydrophilicity. Rosiglitazone emerged from an SAR program on AD 4743 in which the lipophilic cyclohexyl group was replaced by aromatic and polar groups. Replacement with a phenlyurea and conformationally restrained derivatives, such as benzoxazoles gave substantially more potent analogues.

    The minimal effective dose of BRL 48482 was shown to be 3�mol/kg of diet, 300 times the activity of ciglitazone. Altering the lengths of the linking chains led to variations in the spatial separation between the thiazolidinedione and heterocycle. Since the potency was lower for all resulting compounds, it was assumed that BRL 48482 had the optimum spatial separation.

    Replacing either oxygen link with sulfur led to decreased potency as did branching with methyl or phenyl groups. Increasing the bulk of the group at the exocyclic nitrogen or acylating it also led to decreased potency. In the end, three compounds of identical efficacy (ED25 0.3�mol/kg) were isolated.

    BRL 48482 BRL 48552 BRL 49853

    To choose between these compounds, a selectivity screen was developed based on reductions in blood hemoglobin concentration. For BRL 49653, a dose level 100-fold greater than the minimally effective antihyperglycemic dose level had no significant effect on blood hemoglobin concentrations whereas the others showed hemoglobin concentration reductions at dosages only marginally higher than those required to improve glycemic control. Thus BRL 49653, now known as rosiglitazone, was chosen as the preferred antihyperglycemic agent.

    The Pharmacophore

    Rosiglitazone belongs to a class of oral anti-diabetic agents called the thiazolidinediones which seem to be ideally suited for the treatment of type 2 diabetes.. All agents of this class have a thiazolidine-2-4 dione structure as shown. The various agents of this class differ in their side chains which alter their pharmacologic and side-effect profiles.

    The peroxisome proliferator-activated receptors (PPARs) form a subfamily of the nuclear receptor superfamily. The three isoforms of PPARs are ligand-dependent transcription factors that regulate target gene expression by binding to specific peroxisome proliferators response elements (PPREs) in enhancer sites of regulated genes. Each receptor binds to its PPRE as a heterodimer with a retinoid X receptor (RXR). Upon binding an agonist, the conformation of a PPAR is altered and stabilized such that a binding cleft is created and recruitment of transcriptional coactivators occurs. The result is an increase in gene transcription. Through experiments involving dominant negative mutations in human PPAR? it was established that the receptor is indeed implicated in the cause of insulin resistance. Rosiglitazone and other thiazolidinediones are specific high-affinity ligands for PPAR.

    Binding of Rosiglitazone and PPAR?

    Rosiglitazone binding with the PPAR-gamma LBD and SRC-1 in the ternary complex. a, Ribbons drawing showing the ternary complex of PPAR-gamma LBD, BRL 49653, and the LXXLL helix domain of SRC-1. Residues around K301 and E471 that form the ‘charged clamp’ are red, and the LXXLL SRC-1 helix is green. Rosiglitazone (stick diagram) binds in a deep cavity of the protein and provides a network of polar interactions that include the AF-2 domain. b, The secondary-structure elements are shown as a ribbon drawing, with amino acids involved in ligand binding labeled.

    From a study conducted by Young et al. using radioiodinated ligand, it was determined that rosiglitazone bound to PPAR? effectively only in the S-conformation. The IC50 value of the S-entantiomer was 2.1 nm compared to 2770nm of the R-enantiomer.9 The acidic TZD heterocycle forms hydrogen bonds with His 323 on helix 5 and Tyr-473 on the AF2 helix.10

    Pharmacological mechanism of action

    Rosiglitazone reduces insulin resistance by increasing insulin-dependent glucose disposal in skeletal muscle cells and reducing hepatic glucose output by the liver. In subjects with dominant negative PPAR? mutations, adipocyte differentiation was inhibited indicating that PPAR? is necessary in the process of adipocyte differentiation.7 Also, the receptor is present in much greater quantities in adipose tissue than in skeletal or liver tissue. The primary effect of PPAR? is on adipose tissue with secondary insulin-sensitizing effects on skeletal muscle and liver cells. By stimulating glucose uptake into adipocytes through the glucose transporter GLUT-4, PPAR? causes liver and muscle cells to be more sensitive to existing levels of glucose i.e. it decreases insulin resistance.

    Rosiglitazone monotherapy is effective in patients with type 2 diabetes; in studies conducted, it reduced fasting plasma glucose levels by 3.22 mmol/L in 2 mg doses (bd) and by 4.22 mmol/L in 4 mg doses (bd). � cell function was estimated to be improved over baseline by up to 60%.

    Although effective in monotherapy, the insulin sensitizer is often used in conjunction with sulphonylureas or metformin. Sulphonylureas stimulate insulin secretion from � cells and thus treat the relative or absolute insulin deficiency of Type 2 diabetes rather than insulin resistance. Studies demonstrated that endogenous fasting insulin concentrations with rosiglitazone (2mg bd) + sulphonylurea were 6.4 pmol/L lower than those in patients undergoing treatment with just sulphonylurea.13 Metformin, a biguanide, was used in a 12-week trial of rosiglitazone combination therapy; fasting glucose levels decreased from. Because the mechanism of rosiglitazone differs from those of sulphonylurea and metformin, the effects of a combination of the two are additive, possibly synergistic. In addition to drug combination therapy, type 2 diabetes is treated through lifestyle modifications such as weight loss and increased pharmacologic agents which decrease the body’s requirement for insulin.


    RXR ligands have been shown to be effective in activating PPAR?. This is because PPAR? forms a heterodimer with the retinoid X receptor (RXR) that can be activated by both PPAR? and RXR-specific ligands.15 Experiments were conducted to test whether LG100268, an RXR ligand, could enhance transcriptional activation by mutant PPAR?. At moderate concentrations, a combination of PPAR? and RXR ligands induced significanlty greater transcriptional activation than either ligand alone indicating the possibility of synergistic effects.16 Exercise stimulates glucose uptake by muscle cells with normal insulin sensitivity; rosiglitazone therapy in conjunction with exercise improves this synergic action.

    Metabolism: The fate of Rosiglitazone as it journeys through the human body. Rosiglitazone is extensively metabolized; no unchanged drug was detected in the urine in studies conducted using 14C-labeled rosiglitazone. It was rapidly cleared from the plasma in all subjects, being quantifiable only up to 24 hours after dosing. N-demethylation and hydroxylation followed by conjugation with sulfate and glucoronic acid proved to be the major routes of metabolism. In vitro data show that rosiglitazone is predominantly metabolized by the cytochrome P450(CYP) isoenzyme 2C8 with CYP2C9 serving as a minor pathway. The metabolites formed are active but have significantly less activity than the parent compound. Below is a scheme18 proposed for the metabolism of rosiglitazone in humans.

    M10 and M4 together accounted for approximately 35% of the dose excreted over 8 days.18 The scheme proposed is closely similar to that proposed for metabolism in rats and dogs. According to Bolton et al., phase I metabolism in the rat and dog resulted in ring hydroxylation, N-demethylation and oxidative removal of the pyridinylamino function to yield a phenoxyacid derivative19 just as in the proposed scheme for metabolism in humans. There were differences in species in the persistence of the circulating metabolites (measured as total radioactivity), but rosiglitazone’s principal metabolites were accurately predicted from preclinical studies. Unlike the preclinical species, however, the phenoxyacetic acid metabolite M1 was a minor route of elimination in humans, accounting for less than 4% of the dose.18


    A prodrug of rosiglitazone was not found. This result seems reasonable as the pharmacokinetics of rosiglitazone are within an optimum range without modification. It is already 99% bioavailable and none of its metabolites are toxic. Search was conducted with keywords: avandia prodrug, rosiglitazone prodrug, diabetes prodrug, thiazolidinedione prodrug with the search engines PubMed, All Ovid, Google, Lexis-Nexis, ISI Web of Science, Medline, EMBASE Drugs and Pharmacology, and Academic Search Elite.

    Possible Prodrug

    Cytochrome P-450, an electron donor protein for several oxygenase enzymes found on the endoplasmic reticulum of most eukaryotic cells, can oxidize tertiary amines. A carbinolamine is formed which readily decomposes to the secondary amine with loss of formaldehyde.20 By this mechanism a possible prodrug would be rosiglitazone with the nitrogen of the thiazole methylated. The methylation prevents hydrogen

    bonding making the molecule more lipophilic. However, since the H-bonding is necessary for binding to PPAR?, P-450 must demethylate the prodrug before it can be effective. This might delay the onset of action of rosiglitazone which would be useful in some circumstances. The mechanism by which cytochrome P-450 would demethylate the possible prodrug is outlined below.

    Side Effects

    In 26-week clinical trials, the mean weight gain in patients treated with rosiglitazone (8mg daily) monotherapy was 3.5kg. Edema was reported in 4.8% of patients receiving rosiglitazone vs 1.3% of patients on placebo. Decreases in hemoglobin and hematocrit of  1.0 g/dL and 3.3% respectively were observed in clinical trials of rosiglitazone monotherapy as well as in combination with other hypoglycemic agents. There was also a slight decrease in white blood cell count which is probably related to the increased plasma volume. In placebo-controlled trials, 0.2% of rosiglitazone-treated patients have reversible elevations in ALT (>3 times the upper limit of normal), compared with 0.5% of patients on active comparator agents. Headaches, back pain and a slight cough are also minor side effects of rosiglitazone treatment.

    Tolerance to Rosiglitazone

    No indications of tolerance to rosiglitazone due to effects of the drug itself were found. In studies conducted regarding the effects of thiazolidinediones, 75% of the patients exhibited glucose-lowering effects while 25% did not. Analysis of the individual data revealed that those that did not respond to the drug had the lowest levels of insulin secretion at the onset of the study.22 This indicates that rosiglitazone is not effective in the absence of adequate levels of insulin. Other factors that decrease glucose tolerance i.e. increase insulin resistance will cause rosiglitazone to be less effective.

    In a study conducted by Gerben et al., the effects of caffeine on whole-body insulin sensitivity were observed. The calculated insulin sensitivity during caffeine administration was .39 �0.04 compared with 0.46 � 0.04 �mol/kg in the placebo. This decrease in insulin sensitivity of ~15% is close in magnitude to the increase in insulin sensitivity obtained by rosiglitazone23 and may thus be involved in seemed tolerance.

    Searches were conducted on PubMed, All Ovid, Google, Lexis-Nexis, ISI Web of Science, Medline, EMBASE Drugs and Pharmacology, and Academic Search Elite with key words rosiglitazone tolerance, decreased effects of rosiglitazone (thiazolinediones), increasing insulin resistance, avandia tolerance.


    1. Smith, Steve. December 6th, 2001. SMR Drug Discovery Award Lecture. Avandia- targeting type 2 diabetes, the epidemic disease of the 21st century.
    2. DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM: a balanced overview. Diabetes Care 1992;15:318-368.
    3. Cantello BCC, Cawthorne MA, Cottam GP, Duff PT, Haigh D, Hindley RM, Lister CA, Smith SA, Thurlby PL. [[.omega.-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents. J. Med. Chem.; 1994; 37(23); 3977-3985
    4. Thorp JM, Waring WS. 1962. Nature of hepatomegalic effect produced by ethyl-chlorophenoxy-isobutyrate in the rat. Nature 208:856-858.
    5. Smith, Steve. December 6th, 2001. SMR Drug Discovery Award Lecture. Avandia- targeting type 2 diabetes, the epidemic disease of the 21st century.
    6. Cantello BCC, Cawthorne MA, Cottam GP, Duff PT, Haigh D, Hindley RM, Lister CA, Smith SA, Thurlby PL. [[.omega.-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents. J. Med. Chem.; 1994; 37(23); 3977-3985
    7. Chakrabarti R, Vikramandithyan RK, Prem Kumar M, Kumar SKB, Mamidi NVS, Misra P, Suresh J, Hiriyan J, Rao CS, Rajagopalan R. PMT13, a pyrimidone analogue of thiazolidinedione improves insulin resistance-associated disorders in animal models of type 2 diabetes. Diabetes 2002: 4(5):319
    8. Brooks DA, Etgen,GJ, Rito CJ, Shuker AJ, Dominianni SJ, Warshawsky AM, Ardeck R, Paterniti JR, Tyhonas J, Karanewsky DS, Kauffman RF, Broderick CL, Oldham BA, Rafizadeh CM, Winneroski LL, Faul MM, McCarthy JR. Design and Synthesis of 2-Methyl-2-{4-[2-(5-methyl-2-aryloxazol- 4-yl)ethoxy]phenoxy}propionic Acids: A New Class of Dual PPAR/ Agonists. J. Med. Chem 2001; 44 (13): 2061-2064.
    9. Barroso I, Gurnell M, Crowley VEF, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TDM, Lewis H, Schafer AJ, Chatterfee VKK, O’rahilly S. Dominant negative mutations in human PPAR? associated with severe insulin resistance, diabetes mellitus, and hypertension. Nature1999; 402:880-83.
    10. Xu EH, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL, Oplinger JA, Kliewer SA, Gampe RT, McKee DD, Moore JT, Wilson TM. Structural determinants of ligand binding selectivity between the peroxisome proliferators activated receptors. Proceedings of the National Academy of Sciences 2001; 98(24):13919-13924.

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