We use cookies to give you the best experience possible. By continuing we’ll assume you’re on board with our cookie policy

See Pricing

What's Your Topic?

Hire a Professional Writer Now

The input space is limited by 250 symbols

What's Your Deadline?

Choose 3 Hours or More.
Back
2/4 steps

How Many Pages?

Back
3/4 steps

Sign Up and See Pricing

"You must agree to out terms of services and privacy policy"
Back
Get Offer

Rosiglitazone maleate: combating insulin resistance

Hire a Professional Writer Now

The input space is limited by 250 symbols

Deadline:2 days left
"You must agree to out terms of services and privacy policy"
Write my paper

Introduction

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.

Don't use plagiarized sources. Get Your Custom Essay on
Rosiglitazone maleate: combating insulin resistance
Just from $13,9/Page
Get custom paper

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.1

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.

Ciglitazone

Ciglitazone normalizes blood glucose without hypoglycemia and reduces elevated triglycerides and fatty acids4.

Lead Modification: From Ciglitazone to Rosiglitazone

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

increased 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.3

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 in fig 1. The various agents of this class differ in their side chains which alter their pharmacologic and side-effect profiles.

pharmacophore

fig. 1 the glitazones

Further modifications to rosiglitazone to create molecules such as

PMT-13 which are even more potent have been carried out; such

molecules still retain the thiazolidine-2-4 dione structure.5

Non-TZD insulin sensitizers are now being synthesized based on an PMT-13

alkoxy-propionic class of molecules, but these bind to the isoform PPAR? rather than PPAR?6.

The PPAR? Receptor: Rosiglitazone’s means to the end

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.7 Rosiglitazone and other thiazolidinediones are specific high-affinity ligands for PPAR?.8

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. 8

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.11

Combination therapy: Two soldiers are better than one.

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%.12

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 213�46 to 152�35 mg/dL (p<0.005).14 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.

Synergism

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.17

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

Prodrug

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.21

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.

Conclusion

Rosiglitazone, developed through a “screen to lead” technique, by SmithKlineBeecham Pharmaceuticals is now an effective drug against NIDDM. It has been used to treat over 2,500,000 patients as of 2001.1

1 Smith, Steve. December 6th, 2001. SMR Drug Discovery Award Lecture. Avandia- targeting type 2 diabetes, the epidemic disease of the 21st century. http://www.prous.com/smr01/webcast.asp

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.

1 All figures taken from

Smith, Steve. December 6th, 2001. SMR Drug Discovery Award Lecture. Avandia- targeting type 2 diabetes, the epidemic disease of the 21st century. http://www.prous.com/smr01/webcast.asp

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

5 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

6 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.

7 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.

8 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.

9 Young W, Derek BR, Cantello B, Chapman H, Clapham J, Coyle P, Haigh D, Hindley R, Holder J, Kallendar H, Latter A, Lawrie K, Mossakowska D, Murphy G, Cox LR, Smith S. Identificatino of High-Affinity Binding Sites for the Insulin Sensitize Rosiglitazone (BRL-49653) in Rodent and Human Adipocytes Using a Radioiodinated Ligand for Peroxisomal Proliferator-Activated Receptor ?. The Journal of Pharmacology and Experimental Therapeutics 284(2): 751-759.

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.

7 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.

11 Chao L, Marcus-Samuels B, Mason MM, et al. Adipose tissue is required for the antidiabetic, but not the hypolipidemic, effect of thiazolidinediones. Journal of Clinical Investigations 2000; 106:1221-1228.

12 Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, Freed MI Rosiglitazone monotherapy is effective in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 86 (1):280-288 Jan 2001.

13 Wolffenbuttel BH, Gomis R, Squatrito S, Jones, NP, Patwardhan RN. 2000. Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in type 2 diabetic patients. Diabetic Medicine. 17(1):40-47.

14 Fonseca V, Rosenstock J, Patwardhan R, Salzman A. 2000. Effect of metmorfin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 283(13):1695-702.

15 Mukherjee R, Davies PJA, Crombie DL, et al. 1997. Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. Nature 386:407-410.

16 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.

17 Hallsten K, Virtanen K, Lonnqvist F, Sipila H, Oksanen A, Viljanen T, Ronnemaa T, Viikari J, Knuuti J, Nuutila P. Rosiglitazone but Not Metformin Enhances Insulin- and Exercise-Stimulated Skeletal Muscle Glucose Uptake in Patients with Newly Diagnosed Type 2 Diabetes. Diabetes 2002; 51:3479-3485.

18 Cox P, Ryan D, Hollis F, Harris A, Miller A, Vousden M, Cowley H. Absorption, Disposition, and Metabolism of Rosiglitazone, a Potent Thiazolidinedione Insulin Sensitizer, In Humans. Drug Metabolism and Disposition 2000; 28(7):772-780.

18 Cox P, Ryan D, Hollis F, Harris A, Miller A, Vousden M, Cowley H. Absorption, Disposition, and Metabolism of Rosiglitazone, a Potent Thiazolidinedione Insulin Sensitizer, In Humans. Drug Metabolism and Disposition 2000; 28(7):772-780.

19 Bolton GC, Keogh JP, East PB, Hollis FJ and Shore AD. The fate of a thiazolidinedione antidiabetic agent in rat and dog. Xenobiotica 1996; 26:627-636.

20 Silverman, RB. The Organic Chemistry of Drug Design and Drug Action. Academic Press. San Diego. 1992. 140.

21 Avandia. Prescribing information. April 2000. Philadelphia, PA: Smith Kline Beecham Pharmaceuticals.

22 Valiquett T, Balagtas C, Whitcomb R. Troglitazone dose-response study in patients with NIDDM (Abstract). Diabetes 1996; 44 (Suppl. 1):109A.

23 Keijzers GB, De Galan BE, Tack CJ, Smits P. Caffeine can decrease insulin sensitivity in humans. Diabetes Care 2002; 25:364-369.

1 Smith, Steve. December 6th, 2001. SMR Drug Discovery Award Lecture. Avandia- targeting type 2 diabetes, the epidemic disease of the 21st century. http://www.prous.com/smr01/webcast.asp

Cite this Rosiglitazone maleate: combating insulin resistance

Rosiglitazone maleate: combating insulin resistance. (2017, Dec 20). Retrieved from https://graduateway.com/rosiglitazone-maleate-combating-insulin-resistance/

Show less
  • Use multiple resourses when assembling your essay
  • Get help form professional writers when not sure you can do it yourself
  • Use Plagiarism Checker to double check your essay
  • Do not copy and paste free to download essays
Get plagiarism free essay

Search for essay samples now

Haven't found the Essay You Want?

Get my paper now

For Only $13.90/page