Orlistat or tetrahydrolipstatin (Xenical, Hoffmann-La Roche) is a saturated derivative of lipstatin originally isolated from Streptomyces toxytricini. Orlistat (Xenical, Hoffmann-La Roche) is a powerful inhibitor of gastrointestinal lipase and as such, reduces fat absorption. Orlistat acts by binding covalently to the serine residue of the active site of gastric and pancreatic lipases. When administered with fat-containing foods, orlistat partially inhibits hydrolysis of triglycerides, thus reducing the subsequent absorption of monoaclglycerides and free fatty acids. Unlike other weight-reducing drugs it is minimally absorbed and has no effects in the CNS. Xenical is indicated for obesity management including weight loss and weight maintenance when used in conjunction witha reduced-calorie diet. XENICAL is also indicated to reduce the risk for weight regain after prior weight loss. XENICAL is indicated for obese patients with an initial body mass index (BMI) ≥ 30 kg/m2 or ≥ 27 kg/m2 in the presence of other risk factors (eg, hypertension, diabetes, dyslipidemia). In addition to its well established efficacy in achieving modest weight loss, orlistat has been shown to improve glycaemic parameters in obese adults with type 2 diabetes mellitus as well as some features of the metabolic syndrome.

Fenfluramine (former brand names Pondimin, Ponderax and Adifax), also known as 3-trifluoromethyl-N-ethylamphetamine, is an anorectic that is no longer marketed. In combination with phentermine, it was part of the anti-obesity medication Fen-phen. Fenfluramine was introduced on the U.S. market in 1973 and withdrawn in 1997. It is the racemic mixture of two enantiomers, dexfenfluramine, and levofenfluramine. The drug increases the level of serotonin, a neurotransmitter that regulates mood, appetite and other functions. Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter and reversing serotonin transporter function. The drug was withdrawn from the U.S. market in 1997 after reports of heart valve disease and pulmonary hypertension, including a condition known as cardiac fibrosis. It was subsequently withdrawn from other markets around the world. In this small exploratory and retrospective study, remarkably good results were reported on the use of fenfluramine as an add-on medication for controlling seizures in patients with the Dravet syndrome. The side effects were rare and nonserious and did not result in termination of the treatment. It is possible that this drug may have anticonvulsive effects for other severe epilepsy syndromes, especially in those characterized by photosensitive or induced seizures.

Phentermine is an amphetamine that stimulates neurons to release or maintain high levels of a particular group of neurotransmitters known as catecholamines; these include dopamine and norepinephrine. High levels of these catecholamines tend to suppress hunger signals and appetite. The drug seems to inhibit reuptake of noradrenaline, dopamine, and seratonin through inhibition or reversal of the reuptake transporters. It may also inhibit MAO enzymes leaving more neurotransmitter available at the synapse. Phentermine (through catecholamine elevation) may also indirectly affect leptin levels in the brain. It is theorized that phentermine can raise levels of leptin which signal satiety. It is also theorized that increased levels of the catecholamines are partially responsible for halting another chemical messenger known as neuropeptide Y. This peptide initiates eating, decreases energy expenditure, and increases fat storage. Phentermine is indicated in the management of exogenous obesity as a short term (a few weeks) adjunct in a regimen of weight reduction based on caloric restriction. Phentermine hydrochloride is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, the amphetamines. Actions include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for.

Estrone, one of the major mammalian estrogens, is an aromatized C18 steroid with a 3-hydroxyl group and a 17-ketone. It is produced in vivo from androstenedione or from testosterone via estradiol. It is produced primarily in the ovaries, placenta, and in peripheral tissues (especially adipose tissue) through conversion of adrostenedione. Estrone may be further metabolized to 16-alpha-hydroxyestrone, which may be reduced to estriol by estradiol dehydrogenase. It’s used as hameopatic in management of premenopausal and postmenopausal symptoms. In 1929, Butenandt isolated estrone from the urine of pregnant women. Estrone is known to be a carcinogen for human females as well as a cause of breast tenderness or pain, nausea, headache, hypertension, and leg cramps in the context of non-endogenous exposure. In men, estrone has been known to cause anorexia, nausea, vomiting, and erectile dysfunction. Estrone is relevant to health and disease states because of its conversion to estrone sulfate, a long-lived derivative. Estrone sulfate acts as a reservoir that can be converted as needed to the more active estradiol.

Otenabant (CP-945,598) is Pfizer developed as a potent and selective cannabinoid receptor CB1 antagonist with Ki of 0.7 nM, which exhibits 10,000-fold greater selectivity against human CB2 receptor, for treatment of obesity. In clinical trial III Pfizer decided to discontinue the development program based on changing regulatory perspectives on the risk/benefit profile of the CB1 class and likely new regulatory requirements for approval.

Talibegron (ZD2079) is a β3 adrenoceptor agonist and insulin sensitiser. It was developed as a potential treatment for obesity and non-insulin-dependent diabetes mellitus. Talibegron hydrochloride had been in phase II clinical trials by AstraZeneca for the treatment of type 2 diabetes and obesity. However, this research has been discontinued.

Tesofensine (also known as NS-2330) is a novel triple monoamine reuptake inhibitor with intrinsic inhibitory activity on norepinephrine (NE), serotonin (5-HT), and dopamine (DA) transporter function. It was development by NeuroSearch as a potential therapy for Alzheimer's disease (AD) and Parkinson's diseases, but these efforts have been discontinued. In phase II clinical trials with tesofensine in obese individuals, dose-related reductions in body weight, body fat and waist circumference, as well as improvements in other obesity-related endocrine factors were observed and the FDA recently endorsed the phase III trial program for this agent.

Taranabant is a highly selective cannabinoid-1 (CB1) receptor inverse agonist developed by Merck & Co for the treatment of obesity. The Phase III taranabant study involved about 2,400 patients and was to be conducted for two years. In March 2008, after completion of 52 weeks of the study, Merck reported positive results of the drug in conjunction with diet and exercise in obese patients. The patients experienced double the amount of weight loss by taking 2mg of taranabant when compared to the patients treated with placebo. However, in October 2008, the company discontinued the Phase III programme and clinical development of taranabant because of its side effects. The drug showed gastrointestinal and psychiatric side effects such as increased anxiety, depression and irritability. Merck had previously planned to file for regulatory approval with the US Food and Drug Administration in 2008, but subsequently withdrew it.

Sobetirome (3,5-dimethyl-4[(4'-hydroxy-3'-isopropylbenzyl)-phenoxy] acetic acid, also known as GC-1 and QRX-431, is a member of a class of compounds known as selective thyromimetics. It was firstly developed by Thomas Scanlan’s group at the University of California-San Francisco (UCSF) in 1995. Sobetirome binds selectively to the main hepatic form of thyroid hormone (TH) receptor, TRβ1, compared to TRα1, which is principally responsible for thyrotoxic effects on heart, muscle and bone. Sobetirome also preferentially accumulates in liver. It was originally envisaged that sobetirome could be used to stimulate hepatic pathways that lower cholesterol without harmful side effects and might be used in conjunction with statins. Indeed, sobetirome progressed through preclinical animal studies and Phase I human clinical trials with excellent results and without obvious harmful side effects. Sobetirome had been in phase I clinical trials for the treatment of lipid metabolism disorders and obesity. However, this research has been discontinued.

Sodium taurodeoxycholate is a bile salt-related, anionic detergent used for isolation of membrane proteins including inner mitochondrial membrane proteins. It is formed by the conjugation of ursodeoxycholic acid (UDCA) with taurine. Sodium taurodeoxycholate and ursodeoxycholic acid are major constituents of black bear bile, which has been used in traditional Chinese medicine for thousands of years. Bear bile was historically employed to treat a number of diseases including jaundice, summer diarrhea, abdominal pain due to hepatobiliary diseases and gastric malfunction, biliary ascariasis, infectious skin diseases, the common cold, intestinal worms, and inflammation of the throat. Sodium taurodeoxycholate has been shown to inhibit apoptosis by modulating mitochondrial membrane perturbation and pore formation, B cell lymphoma 2 (Bcl-2)-associated protein X (BAX) translocation, cytochrome c release, and caspase activation. Sodium taurodeoxycholate inhibits amyloid beta (Ab)-induced apoptosis and attenuates the endoplasmic reticulum (ER) stress, which are thought to be key components of the pathological process in certain diseases. In clinical studies, Sodium taurodeoxycholate is shown to be very safe with oral administration of 1500 mg/day for up to 6 months. In a more recent clinical study, a dose of 1750 mg/day for up to 4 weeks was well tolerated in healthy obese persons. One of the major adverse effects of Sodium taurodeoxycholate is diarrhea. Based on the related information from ursodeoxycholic acid, other gastrointestinal side effects are possible including abdominal pain, flatulence, nausea, dyspepsia, and anorexia.