Dabhade Sanjay et al NEW DRUG TARGETS TO TREAT THE

NEW DRUG TARGETS TO TREAT THE OBESITY

1 2 2 1 3 IJCRR Dabhade Sanjay , Dabhade S.S. , Tiwari S.A. , Rane B.T. , Meenakshi Sable Vol 05 issue 02 1 Section: Healthcare Dept of Pharmacy, Dr. D Y Patil Medical College and Hospital, Pimpri, Pune, India 2 Category: Review Dept of Pharmacy, B J M edical College and Hospital, Pune, India Received on: 19/11/12 3Dept of Physiology, B J Medical College and Hospital, Pune, India Revised on: 07/12/12 Accepted on: 31/12/12 E-mail of Corresponding Author: [email protected]

ABSTRACT Background: The incidence of obesity is increasing dramatically to epidemic proportions. There are few approved anti-obesity pharmacological treatments and their modest efficacy and safety concern. Presently two drugs approved by US FDA for treatment of obesity are and . Objective: The aim of this review is to discuss the new pharmacological agents that are under development and that may be eventually used for treatment of obesity. Low doses of and phentermine: The rational for combining topiramate with phentermine is to minimise the required dose of each of the medication thereby opening up more than one pathway to satiety in hope of achieving great efficacy. and Naltriaxone: Monotherapy with bupropion shown weight loss of 2.8 kg at 52 weeks and this does not meet FDA criteria for an antiobesity drug. Naltriaxone alone is associated with minimal weight loss. Combination would be associated with weight reduction. and Bupropion: Zonisamide induces weight loss as a side effect. It was thought that bupropion when added to zonisamide decreases the depressive and sedative properties associated with zonisamide while the latter might reduce the likelihood of bupropion-induced seizures. Liraglutide: Victoza (liraglutide) is a once-daily version of the new-generation GLP-1(glucagon like peptide) analogs. Victoza reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake. Cetilistat: an inhibitor of pancreatic lipase, an that breaks down triglycerides in the intestine. This drug is similar to the currently FDA-approved drug orlistat. Phase III trials of cetilistat are currently under way in Japan. TTP 435:TTP435 is a potent and selective inhibitor of AgRP. TTP435 was shown to reduce food intake and body weight gain, reduce fat composition, and reduce insulin levels in a dose-dependent fashion. GSK 598809: GSK 598809 is a D3 antagonist that blocks dopamine. It is thought that blocking dopamine may reduce the intake of foods high in fat and sugar. Conclusion: Many factors have mitigated against active drug development, including the poor safety and efficacy of previous antiobesity drugs. The new generation of antiobesity drugs offers hope for the management of obesity, although no single agent is likely to be a solution. Keywords- phentermine, , orlistat, obesity

INTRODUCTION all societies of the world and with it come the The incidence of obesity is increasing major pathological complications including dramatically to epidemic proportions in almost hypertension, type 2 diabetes.1 DM,

Int J Cur Res Rev, Jan 2013 / Vol 05 (02) Page 71 Dabhade Sanjay et al NEW DRUG TARGETS TO TREAT THE OBESITY osteoarthritis, dyslipidemia, obstructive sleep Orlistat can have significant gastrointestinal side apnoea and some cancers.2 effects, especially if dietary fat intake is much Many of these diseases can be prevented or more than 30% of total daily caloric intake; this ameliorated with a reduction in body weight. limits its tolerability in many patients.7 Despite dramatic advances in our understanding Limitations: valvulopathy: fenfluramine and of central regulation of energy balance and , obesity, there are few approved antiobesity Abuse potential and psychiatric side effects: pharmacological treatments and their modest , efficacy and safety concern.3 Cardiac adverse events: . 8 Regulatory authorities European Union: a mean weight loss of 10% HISTORY OF ANTIOBESITY MEDICINE from the baseline after 1 year of treatment. FDA FDA US FDA : >5 % placebo subtracted weight loss Drugs approval withdrawal difference after 1 year. 4 date date Obesity is a fetal chronic relapsing disease, the Phentermine 5/1959 Still in use most prevalent of 21st century .Despite rigorous Fenfluramine 6/1973 9/1997 attempts at behavioural change, many patients are Dexfluramine 4/1996 9/1997 Orlistat 4/1999 Still in use unable to achieve long term maintenance of sibutramine 11/1997 10/2010 weight loss through lifestyle alone and the Rimonabant 6/2006 10/2008 growing number of patients forced to undergo bariatric surgery points the need for effective New targets have been identified as more drug treatments.5 research has been performed to understand the So there is need of continuous dialogue between complex circuitry controlling energy obesity researchers, pharmaceutical industries homeostasis. The aim of this review is to discuss and regulatory authorities to stimulates research the new pharmacological agents that are under and drug development based on the clinical need development and that may be eventually used for of the patients and recognising the true clinical treatment of obesity. endpoints should be the priority to allow Hypothalamus and the central control of appropriate risk: benefit assessment.6 There are feeding and energy homeostasis two drugs approved by US FDA for treatment of The hypothalamus is the key processing area obesity 7, 3. within the brain for the integration of numerous Phentermine, approved in 1959, is the most signals related to energy homeostasis. Peripheral commonly prescribed antiobesity agent in the signals of satiety are integrated and passed on to United States. other areas of the brain via nuclei in the Orlistat, approved in 1999, is an oral lipase hypothalamus inhibitor that reduces absorption of dietary fat.

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Circuits implicated in the central control of feeding. AcbSH, nucleus accumbens shell; AgRP, agouti gene-related peptide; ARC, arcuate nucleus; CART, cocaine- regulated transcript; CCK, cholecystokinin; CRH, corticotrophin releasing hormone; LHA, lateral hypothalamus; α-MSH, alpha-melanocyte stimulating hormone; MCH, melanin-concentrating hormone; MC4R, melanocortin 4 receptor; NPY, neuropeptide Y; NTS, tractus solitari; ORX-orexin (hypocretin); OXY, oxytocin; POMC, pro-opiomelanocortin; PVN, periventricular nucleus.

Peripheral signals from adipose stores, the MCH/ORX activity, leading to satiation and a gastrointestinal tract and endocrine system termination of feeding.6 influence the activity of neurons within the Combination Therapy arcuate nucleus of the hypothalamus. When fat Low doses of topiramate and phentermine stores are reduced and energy levels are low, (Qnexa): hunger signals mediated via an increase in the gut Phentermine, an amphetamine derivative, has hormone, ghrelin, and reductions in insulin, been on the market for more than 30 years for glucose, leptin and cholecystokinin (CCK) cause short-term treatment of obesity. increases in the activity of both neuropeptide Y Topiramate has been approved for migraine (NPY) and agouti-related protein (AgRP) prophylaxis and the treatment of seizure neurons, which in turn leads to decreased activity disorders. Early studies of topiramate, when used of the melanocortin system, leading to dis- for other indications, demonstrated an unexpected inhibition of melanin-concentrating hormone weight-loss benefit. Topiramate is a weak (MCH) and orexin (ORX) signalling producing a carbonic anhydrase inhibitor, inhibits isoforms II marked orexigenic effect. Following a meal the and IV; it also modulates GABA –A receptors reverse occurs, with high levels of glucose, which causes inactivation of Na channels. The insulin, CCK and reduced ghrelin levels leading modulation of γ-amino butyric acid may have a to increases in pro-opiomelanocortin (POMC), in role in the reduction of food intake.9 turn increasing α-melanocyte-stimulating The rational for combining topiramate with hormone (α-MSH) release and decreasing phentermine is to minimise the required dose of

Int J Cur Res Rev, Jan 2013 / Vol 05 (02) Page 73 Dabhade Sanjay et al NEW DRUG TARGETS TO TREAT THE OBESITY each of the medication thereby opening up more requested additional information regarding than one pathway to satiety in hope of achieving teratogenecity and company will continue to great efficacy. work with FDA in an effort to secure approval. In oct.2010 ,the FDA did not approved QNEXA VIVUS has completed three Phase III studies of because of the elevated heart rate associated with Quinexa. Results of this trial are given in the its use , teratogenic potential of drug .In Jan. table. 2011 VIVUS announced that FDA had

VIVUS PHASE III TRIALS of Qnexa

EQUATE EQUIP CONQUER Duration 28 56 56 (Wks) BMI (kg/m2) 30-45 >42.5 >36.3

End points >5% >5% >5% (Wt.loss) No.of pts 756 1267 2487

Dropout rate 31% 41,31,36%

Bupropion and Naltriaxone (Contrave) weeks as single agent and this does not meet A dual antiobesity agent .It is combination of FDA criteria for an antiobesity drug.10 As bupropion and naltriaxone. Buproprion is monotherapy naltriaxone is associated with inhibitor of DA and NA used for treating minimal weight loss.3 depression and inducing smoking cessation. Thus combining these two agents would associate During initial trials it was noted that it suppressed with clinically meaningful and sustained pattern appetite and food craving. Monotherapy with of weight reduction. bupropion shown weight loss of 2.8 kg at 52

Bupropion stimulate

arcuate nucleus negative- release of B- feedback ++POMC endorphin loop Naltriaxone release activating opioid α-melanocyte receptors on POMC stimulating hormone and controlling further POMC firing.

Anorexia early plateauing of the effects of bupropion,

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In a double-blind placebo-controlled study, The patients were randomized to one of six arms: enrolling 419 obese subjects BMI 30–40 kg/m2g Two groups: 1) Bupropion IR 360 mg + over a period of 24 weeks. The subjects were Zonisamide SR 120 mg 2) Bupropion IR 360 receiving one of the following: mg + Zonisamide SR 360 mg, Placebo, 48 mg alone, Bupropion Three single-treatment groups 1) Bupropion IR slow-release (SR) 400 mg alone, or combinations 360 mg, 2) Zonisamide SR 360 mg, 3) of Bupropion 400 mg with varying doses of Zonisamide SR 120 mg and 4) Placebo. Naltrexone (16 mg, 32 mg, and 48 mg). 11 The combination therapy containing zonisamide At 24 weeks, the average weight loss in each of 120 mg, 360mg given weight loss of 6.1% and the groups was as, 0.9 kg 1.1 kg; 2.6 kg; for alone 7.5%. No patient experienced serious adverse drug and events due to Empatic. The occurrence of With (400 mg Bupropion) + (Naltrexone 16 mg, depression, impaired cognitive function, anxiety, 32mg, 48mg, ) 5.1 kg; 5.1 kg, and 4kg and suicidality were not significantly different respectively. between the placebo and Empatic groups. At a 48-week extension time point, the weight Plans for phase III Empatic trials have not yet loss increased to 7.4 kg, 8.2 kg, and 10 kg, been announced. respectively, in the three combinations treatment Pramlintide/metreleptin groups. Leptin is a hormone produced by adipocytes, and These data endorse the hypothesis that two drugs early studies linked leptin deficiency in mice working synergistically and in combination leads to massive obesity. At first here was hope provide greater weight loss than either of them that leptin would be a successful treatment option singly. to combat obesity. However, many clinical trials Zonisamide and Bupropion (Empatic) failed to demonstrate any benefit of treatment Empatic is the combination drug of zonisamide with recombinant human leptin. In fact, leptin and bupropion. Clinically, it has been shown to levels have been shown to be up to 10-fold higher induce weight loss as a side effect. However, a in obese individuals. possible mechanism is sodium channel Amylin is a peptide hormone with both glucose- modulation and enhancement of dopamine and regulatory and anorexigenic actions. Amylin is serotonin neurotransmission, potentially resulting stored in the pancreatic A-cell secretory vesicles in weight loss. and secreted in response to food intake. It acts in Bupropion, has also been linked to weight loss. the hindbrain area postrema and central nucleus With this drug, the weight loss is thought to be of the amygdala to reduce food intake, by acting caused by a drug-induced increase in the level of as a satiety signal. 2 dopamine, which could lead to a reduction in Clinical studies have shown that pramlintide, appetite. 12 The addition, it was thought that (Synthetic amylin) currently approved in the bupropion when added to zonisamide decreases United States for the treatment of type 1 or 2 the depressive and sedative properties associated diabetes, leads to reduction in food intake and with zonisamide while the latter might reduce the body weight in obese humans.13 likelihood of bupropion-induced seizures. 7 The results of mechanistic studies in rats pre- In September 2009, Orexigen released data from treated with amylin suggested that leptin a 24-week phase IIb double-blind, placebo- signaling within the hypothalamus and caudal controlled trial of Empatic in 729 obese patients hindbrain may modulate the observed weight-loss with BMI range 27–45 kg/m2. synergy, such the presence of amylin may

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“prime” the hypothalamus to respond better to Drugs Wt.Loss Valvulopathy Valvulopathy leptin. (12Wks) (24Wks) (52Wks) In a 28-week, double-blind, placebo-controlled 4.5% 2.5% 2.9% 2 10 mg BD study enrolled 608 obese BMI 27–45 kg/m . lorcaserin 2.5% 2.5% 2.5% After a 1-week placebo lead-in period, the 10 mg OD subjects were randomized to twice-daily therapy placebo. 1.5% 1.9% 0.5% with eight regimens: (i) placebo + placebo, (ii) In January 2011, the manufacturer of the drug pramlintide 360 µg + placebo, (iii) metreleptin 5 announced that discussions with the FDA to mg + placebo, (iv) pramlintide 180 µg + finalize protocols for action designed to address metreleptin 2.5 mg, (v) pramlintide 180 µg + the issues raised by the FDA, and that it hopes to metreleptin 5 µg, (vi) pramlintide 360 µg + resubmit the new drug application for lorcaserin metreleptin 1.25 mg, (vii) pramlintide 360 µg + by the end of 2011. metreleptin 2.5 mg, or (viii) pramlintide 360 µg + Liraglutide: GLP-1 is a humoral gut peptide that metreleptin 5 mg. improves insulin secretion, and the currently The magnitude of the weight loss was found to be available analogs have been approved for the dependent on dose and baseline BMI. Treatment treatment of diabetes. GLP-1 also delays gastric with the highest pramlintide + metreleptin doses emptying and suppresses appetite, resulting in had an average weight loss of 11% (P < 0.01), decreased energy intake and weight loss. when compared with placebo group (1.8%) and Exenatide and liraglutide are FDA approved in the groups that received either of the agents GLP-1 analog given DM. singly. In a double-blind placebo-controlled 20-week Monotherapy in Phase II/III Trials trial with open-label orlistat comparator in 19 Lorcaserin Lorcaserin is a 5HT-2C receptor sites in Europe. 564 individuals were randomly agonist. Fenfluramine, a previously marketed non assigned, to one of four liraglutide doses (1·2, selective 5HT agonist, was highly successful in 1·8, 2·4 or 3·0 mg, n=90-95) or to placebo (n=98) inducing weight loss. Fenfluramine targeted administered once a day subcutaneously, or 5HT-2C in addition to 5HT-2B and 5HT-2A. It orlistat (120 mg, n=95) three times a day orally. has been seen that 5HT-2A receptors are All individuals had a 500 kcal per day energy- hallucinogenic14 where as 5HT-2B receptor deficit diet, including the 2-week run-in. An 84- activation is associated with the development of week open-label extension followed.15 valvulopathy and primary pulmonary Mean weight loss with liraglutide was 4·8 , 5·5 , hypertension. 6·3 , and 7·2 kg respectively as compared with Lorcaserin have a high affinity for the 5HT-2C 2·8 kg and 4·1 kg with placebo and orlistat. subtype and very less for 5HT-2A and 5HT-2B; Nausea and vomiting more in liraglutide than in therefore become a target of interest. placebo, but mainly transient and rarely led to DM patients who were overweight or obese. discontinuation of treatment. (N=604) "This is one that is fulfilling a true medical need in the field of medical obesity -- where people are either very obese, or are obese and have pre- diabetes or other metabolic disturbances," Krogsgaard said. Victoza (liraglutide) is a once-daily version of the new-generation GLP-1 type of drug which

Int J Cur Res Rev, Jan 2013 / Vol 05 (02) Page 76 Dabhade Sanjay et al NEW DRUG TARGETS TO TREAT THE OBESITY stimulates cells to release insulin when blood 5HT, DA, and NA.Originally, this drug was sugar levels are high. developed for the treatment of Alzheimer's and Semaglutide, a once-weekly GLP-1 analogue, Parkinson's diseases, and it was noted in clinical Semaglutide, is based on a different molecule trials that there was a persistent weight loss in than Victoza, has finished phase II trials. patients . The drug is believed to induce weight Taspoglutide, under development by Roche reduction through both appetite suppression and Holding AG and Ipsen SA, is another GLP-1 increased thermogenesis. drug for type-2 diabetes.16 A phase II proof-of-concept study was conducted Novo Nordisk remains committed to the by Astrup and colleagues. This randomized, development of a longer-acting GLP-1 analogue. double-blind, placebo-controlled study enrolled Victoza lowers blood glucose by stimulating the 203 subjects with baseline BMI 30–40 kg/m2. release of insulin and lowering of glucagon The subjects were randomized to receive 24 secretion when blood sugar levels are high and weeks of treatment with 0.25, 0.5, or also by slowing gastric emptying. Victoza also 1 mg, or placebo, after a 2-week run-in period. reduces body weight and body fat mass through Analysis demonstrated that the weight reductions mechanisms involving reduced hunger and were dose-dependent.The weight losses of 4.7, lowered energy intake. Victoza is a once-daily 9.1, and 10.6 kg, respectively. injection taken any time of day independent of Adverse effects of tesofensine include dry mouth, meals. nausea, dizziness, constipation, and abdominal Cetilistat: Is an inhibitor of pancreatic lipase, an pain. There was a notable dose-dependent enzyme that breaks down triglycerides in the increase in heart rate up to 8.5 beats per minute at intestine. This drug is similar to the currently the highest dose (1.0 mg). In addition, there was a FDA-approved drug orlistat. 1–2 mm Hg increase in blood pressure that was orlistat's gastrointestinal side effects are a not statistically significant. principal cause for discontinuation, cetilistat may Given these findings, further phase III trials become a preferred lipase inhibitor for achieving might limit the dose to 0.25 and 0.5 mg so as to weight loss. Phase III trials of cetilistat are reduce the impact on heart rate and blood currently under way in Japan. pressure.18 Evidence of the safety and efficacy of cetilistat Preclinical data from diet-induced obese rats has been established through extensive Phase I supported the hypothesis that tesofensine reduces and Phase II clinical trials in Europe, the US and body weight. Japan in over 1,000 subjects (over 800 subjects In phase II clinical trials with tesofensine in on active drug). In a second Phase IIb study obese individuals, dose-related reductions in involving 612 clinically obese diabetic patients, body weight, body fat and waist circumference, along with weight loss Cetilistat was also shown as well as improvements in other obesity-related to cause statistically significant reductions in endocrine factors, were observed. HbA1c. Furthermore, the proportion of subjects Neuro Search has decided that a phase 3 program discontinuing treatment for adverse events was including two obesity studies of one year each is lower with cetilistat than with placebo and with the best way to proceed. This phase 3 program Orlistat, confirming earlier studies showing that must also include a study for more than a two cetilistat has a superior tolerability profile. year period in order to determine the drug's Cetilistat has begun a Phase III trial in Japan.17 cardiovascular safety profile. Tesofensine: Tesofensine is a triple monoamine : NPY (neuropeptide Y) stimulates reuptake inhibitor that blocks the reuptake of food intake, inhibits energy expenditure, and

Int J Cur Res Rev, Jan 2013 / Vol 05 (02) Page 77 Dabhade Sanjay et al NEW DRUG TARGETS TO TREAT THE OBESITY increases body weight by activating the centrally acting NPY to its Y5 receptor, thereby hypothalamic NPY receptors Y1 and controlling energy balance and food Y5.Velneperit, a once-daily, oral neuropeptide consumption. Y5 receptor antagonist, blocks the binding of RCT study: BMI 30–45 kg/m2 (N=656) Reduced-calorie diet regimen(800 kcal/day) to all subjects for 6-week Drugs Diet Duration Weight Adverse Effects Reduction(kg) Velneperit 800 54 3.8 Nasopharyngitis, mg OD 800 weeks. URTI, Sinusitis, Velneperit kcal/day 54 not reported headache. 1,600 mg OD weeks. Mild decreases Placebo 54 0.8 in Hematocrit, weeks. Hb%,RBCs ,

In a double-blind, multi-center , randomized, to 9 hrs. after drug administration relative to parallel-group study to assess the efficacy and placebo. Obinepitide is under development. safety of 400 mg of velneperit (S-2367) and 120 Early-Phase Drugs (Phase I) mg of orlistat administered Individually or TTP 435: Agouti-related protein (AgRP) is a combined orally three times per day with a neuropeptide produced in the arcuate nucleus of reduced calorie diet (RCD) in obese subjects . the hypothalamus. It is coexpressed with NPY Results of this trial are same as of orlistst in and works by increasing appetite and decreasing relation to weight loss.20 metabolism and energy expenditure. Shinogi has completed the phase II trials, and TransTech Pharmaceutical identified TTP435 as planning for phase III trials is under way. a potent and selective inhibitor of AgRP. In vivo, Obinepitide: Obinepitide is a synthetic analogue TTP435 is orally bioavailable, with high brain of two naturally occurring human hormones: penetration. In several studies of animal models PYY3-36 and pancreatic polypeptide. These of obesity ranging in duration from overnight hormones are normally released during a meal administration to 4-week treatment, TTP435 was and are known to play a role in the regulation of shown to reduce food intake and body weight food intake and appetite, acting as satiety signals. gain, reduce fat composition, and reduce insulin Initial studies in humans have shown that levels in a dose-dependent fashion. TTP435 is infusion of PYY3-36 reduced food intake in both currently being assessed in obese subjects in obese and lean subjects. Obinepitide's unique phase II clinical trials. characteristic is that it targets both the Y2 and Y4 ZGN-433: ZGN-433 is a methionine receptors without showing an affinity for the Y1 aminopeptidase 2 inhibitor. Originally developed receptor and Y1 receptor is associated with as a treatment for solid tumors, it was initially cardiovascular side effects. thought to block angiogenesis and reduce adipose In March 2006, 7TM Pharmaceutical announced tissues by blocking blood supply. However, that positive results from obinepitide's proof-of- administration of the drug caused profound concept phase I/II study. Subcutaneous injections weight loss in mice, which thereafter achieved of once- and twice-daily obinepitide were well ideal body weight. The drug may play a role in tolerated and inhibited food consumption for up altering the mechanism by which the body metabolizes fat. In dogs receiving ZGN-433,

Int J Cur Res Rev, Jan 2013 / Vol 05 (02) Page 78 Dabhade Sanjay et al NEW DRUG TARGETS TO TREAT THE OBESITY weight loss is associated with improved glycemic subjects with obesity. The study was scheduled to control and an apparent reduction in demand for be completed in mid-2011; no further data have insulin secretion. been released. In January 2011, Zafgen reported positive results Ezlopitant: Ezlopitant is a neurokinin receptor-1 from its phase Ib study using ZGN-433. antagonist that has been implicated in both A double-blind, placebo-controlled, multiple- learned appetitive behaviours and addiction to ascending-dose study was performed in women alcohol and opioids. Recent evidence from rodent with BMI 32–35 kg/m2, with 24 subjects enrolled studies suggests that ezlopitant reduces the in the core study. appetite for sucrose, thereby decreasing the Primary objective: to evaluate the safety and consumption of sweetened foods and drinks. It tolerability of the compound. has been suggested that sweet foods and drinks Second objective: to obtain information on can be addictive in the same way as alcohol; this weight loss in subjects exposed to eight doses of drug may therefore have a role in obesity IV ZGN-433 administered over 4 weeks. treatment. Further studies have yet to be done.23 Subjects receiving ZGN-433 had a reduction in To evaluate the selectivity of the NK1-receptor median body weight of 1 kg per week and 3.1% antagonist in decreasing consumption of of initial body weight over 26 days. In addition, sweetened solutions, they compared the effects of there was a decline in hunger, 38% reduction in ezlopitant on , saccharin-, and sodium triglyceride levels, and 23% reduction in LDL chloride (NaCl) solution consumption. Ezlopitant cholesterol. Zafgen plans to initiate phase IIa decreased intake of saccharin, but had no effect studies in 2011.21 on water or salty solution consumption. PP 1420: PP 1420 is a pancreatic polypeptide Thyroid hormone receptor agonists analog that is thought to increase satiety. Thyroid hormone affects in a myriad of Previous studies of PP1420 have shown that biological processes such as development, injections of human PP have the effect of growth, and metabolic control. Triiodothyronine reducing appetite and food intake. Human PP has (T3) is the biologically active form of thyroid a short half-life. PP 1420 is a synthetic form of hormone that acts through nuclear receptors, TRα PP with a longer half-life. Phase I trials have and TRβ, regulating gene expression. The been completed by Wellcome Trust, but the distribution of these receptors is heterogeneous results have not yet been released.22 amongst the different tissues, it is not surprising GSK 598809: GSK 598809 is a D3 antagonist that some physiological effects of T3 are isoform that blocks dopamine. It is thought that blocking specific. For example, while TRα is the dominant dopamine may reduce the intake of foods high in receptor in the brain and skeletal system and fat and sugar, and may be a potential treatment mediates most of the synergism between T3 and option for compulsive overeaters and/or binge the sympathetic signaling pathway in the heart, eaters. The medication is being developed for the TRβ is abundant in liver and is probably the treatment of substance dependence and other isoform that mediates most of the T3 effects on impulsive disorders. GlaxoSmithKline is lipid metabolism. Thus, it makes sense to develop currently completing phase I study designed to compounds that selectively act on either one of examine the behavioural and physiological the TRs, allowing for the activation of specific effects of a single dose of GSK 598809 on food T3-dependent pathways. The available studies reward and reinforcement in relation to food- indicate that achieving selective activation of seeking behaviour under conditions of fasting, different TR-mediated pathways is a promising using neurocognitive and metabolic end points in strategy for treating lipid disorders and obesity.

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GC-1, a selective TRβ agonist, when cancel out the adipogenic effects of PPAR ϒ administered to rats, demonstrated a agonism.26 normalization of serum cholesterol and PPAR-γ coactivator-1 α: Peroxisome triglyceride levels. In addition, GC-1 was found proliferator-activated receptor-γ coactivator to accelerate energy expenditure in rats and lower (PGC)-1α is a member of a family of body weight in primates without cardiac side transcription coactivator that plays a central role effects. The accelerated metabolic rate was in the regulation of cellular energy metabolism. It followed by a decrease in fat but not in lean mass. is strongly induced by cold exposure, linking this In other studies, KB2115, a selective TRβ environmental stimulus to adaptive agonist, was administered to moderately thermogenesis. It participates in the regulation of overweight and hypercholesterolemic human both carbohydrate and lipid metabolism. It is subjects. It was found to be safe and well highly likely that PGC-1α is intimately involved tolerated, and it caused a 40% lowering of both in disorders such as obesity, diabetes, and total and LDL cholesterol. Phase II trials are cardiomyopathy. Its regulatory function in lipid under way to investigate the efficacy of TRβ metabolism makes it an inviting target for receptor agonists in treating dyslipidemia, but pharmacological intervention in the treatment of they may become a potential target for obesity and Type 2 diabetes.27 antiobesity treatment soon 24 PGC-1α also interacts with other nuclear 11β-HSD1 inhibitor: 11β-HSD1 is a hormone receptors such as PPAR-α, retinoic acid bidirectional enzyme that interconverts receptor, and thyroid receptor in BAT to enhance hormonally inactive cortisone to cortisol. the expression of brown fat-specific uncoupling Preclinical animal studies have shown proof of protein 1 (UCP1) . UCP1 action leads to concept, with improved glucose tolerance and dissipation of the proton gradient and the weight reduction reported in many diabetic and uncoupling of oxidative phosphorylation, thereby obese mouse models treated with 11β-HSD1 increasing heat production. inhibitors. Phase I and II clinical data reported at : Metformin is a biguanide that is the American Diabetes Association's Scientific approved for the treatment of diabetes mellitus, a Sessions in June 2008 were equally disease that is exacerbated by obesity and weight encouraging.25 gain. Although, the cellular mechanism for the PPAR gamma (ϒ): PPAR ϒ plays a major role effects of metformin are poorly understood. in differentiation of preadipocyte to adipocyte, It has three effects at the clinical level--- the process of adipogenesis. Thus PPAR ϒ 1) It reduces hepatic glucose production, which is agonists like pioglitazone enhance differentiation a major source of circulating glucose. of adipocyte which caused weight gain in animals 2) It reduces intestinal absorption of glucose, and humans. which is a second source of circulating glucose. PPAR modulators are to develop agents that 3) It increases the sensitivity to insulin, thus modulate PPAR ϒ in such a way that the increasing peripheral glucose uptake and compounds improve insulin sensitivity without utilization. any promotion of weight gain. Metformin has been associated with significant Another approach to try to overcome the increase weight loss when compared to sulfonylureas or in body weight seen with full PPAR ϒ agonists is placebo. to develop agonists that act on two or all three of Campbell et al. compared metformin and the PPARs, the hypothesis stimulating PPAR δ, glipizide (Mylan, Morgantown, WV) in a PPAR ϒ will activate activation and randomized double-blind study of Type II

Int J Cur Res Rev, Jan 2013 / Vol 05 (02) Page 80 Dabhade Sanjay et al NEW DRUG TARGETS TO TREAT THE OBESITY diabetic individuals who had failed on diet. The 2. Zigman , Endotext.com-obesity,New 24 subjects receiving metformin lost weight and molecular targets for the treatment of obesity, had better diabetic control of fasting glucose and August 19,2003, online glycohemoglobin than did the glipizide group. 28 3. Frank L.Greenway,M.J.Whitehouse,Maria In a double-blind placebo-controlled trial in Guttadauria, James W Anderson , Rational subjects with the insulin resistance syndrome, design of a combination medication for metformin also increased weight loss. Fontbonne treatment of obesity. Obesity:17(1),30- et al. reported the results from the BIGPRO 39,2008 study, a 1-yr French multicenter study that 4. Tim C. Kirkham,Endogenous cannabinoids:a compared metformin with placebo in 324 middle- new treatment of obesity . Am.J.Physiol aged subjects with upper body obesity and the Regul Integr comp physiol 284:R343- insulin resistance syndrome. The subjects on R344,2003 metformin lost significantly more weight (1–2 5. N.Finer, New targets for obesity kg) than the placebo group. Although metformin pharmacotherapy –developing anti-obesity may not give enough weight loss to receive an drugs that do not necessarily produce weight indication from the USFDA for treating obesity, loss. ©2011 International association for the it certainly deserves consideration in obese Type study of obesity .Clinical obesity1,61 II diabetic individuals who have failed diet and 6. Bruce J Sargent and Nicholas A Moore.New exercise treatment for their diabetes, and it has central targets for the treatment of obesity been used in children .29 .British J Clin Pharmacology:68(6),82-860 Dec.2009 CONCLUSION 7. AG Powell,CM Apovion,LJ Aronne New The vast gap in the current pharmacological drug targets for treatment of obesity ,Clin treatment options for obesity is surprising given Pharmacol Therapeutics 90(1)40-50,2011 the high prevalence and economic burden of 8. James WP et al ,SCOUT investigators Effect obesity. Many factors have mitigated against of sibutramine on cardiovascular outcome in active drug development, including the poor overweight and obese subjects NEJM safety and efficacy of previous antiobesity drugs. 363:(905)917-917(2010) However, compelling targets are now on the 9. Gadde km ,Effects of low dose controlled horizon .The new generation of antiobesity drugs release phenteramine plus topiramate offers hope for the management of obesity, combination on weight & associated although no single agent is likely to be a panacea. comorbidities in overweight and obese adults If sustained success is to be achieved, obesity will (CONQUER):a randomised placebo need to be managed like many other chronic controlled Phase 3 trial Lancet 377,1341- diseases, with combination therapies and long- 1352,2011 term treatment. 10. Li,zet et al, Meta analysis: pharmacologic treatment of obesity , Ann of internal REFERENCES medicine 142,532-46,2005 1. Paul F.Pilch and Nils Bergenhem, 11. Kishore M Gadde, Gretchen M Yonish, pharmacological targeting of adipocytes /fat Mariko S Foust, H Ryan Wagner metabolism for treatment of obesity and Combination therapy of zonisamide and diabetes, Molecular Pharmacology 70:779- bupropion for weight reduction in obese 78,2006 women: a preliminary, randomized, open- label study. The Journal of clinical psychiatry

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