A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys.

Fisher, Michael H.; Amend, A.; Bach, Thomas; Barker, JoAnn; Brady, Edward J.; Candelore, Mari R.; Carroll, Dominic; Cascieri, Margaret A.; Chiu, Shuet Hing Lee; Deng, Liping; Forrest, Michael J.; Hegarty-Friscino, Bonnie; Guan, Xiao-Ming; Hom, Gary J.; Hutchins, Jennifer E.; Kelly, Linda; Mathvink, Robert J.; Metzger, Joseph M.; Miller, Randall R.; Ok, Hyun; Parmee, Emma R.; Saperstein, Richard; Strader, Catherine D.; Stearns, Ralph A.; MacIntyre, D. Euan

doi:10.1172/jci2496

Cited by 111 publications

(50 citation statements)

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“…In rodents [68,69], dogs [70] and rhesus monkeys [71] 3-adrenoceptor agonists not only activate thermogenesis but, when given repeatedly, they increase the capacity of brown fat to respond to acute activation. Moreover, in phaeochromocytoma, an adrenal medulla neuroendocrine tumour, over-secretion of noradrenaline and adrenaline causes a marked increase in brown adipose tissue mass in humans, associated with reduced body fat content [72,73].…”

Section: Brown Adipose Tissuementioning

confidence: 99%

Horizons in the Pharmacotherapy of Obesity

Arch

2015

Curr Obes Rep

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Abstract:Obesity drugs have had a chequered history. In the recent past, only the low efficacy, pancreatic lipase inhibitor orlistat was available worldwide and it was little used. The 5HT2C agonist lorcaserin, and two combinations of old drugs have been approved in the United States but not in Europe. The diabetes drug liraglutide has been approved in both the US and Europe and seems likely to be most widely accepted. In view of regulators' caution in approving obesity drugs, some (like beloranib) may initially be progressed for niche obesity markets. New drug targets have been identified in brown adipose tissue with the aim of not only activating thermogenesis but also increasing the capacity for thermogenesis in this tissue. Attempts are being made to match the efficacy of bariatric surgery by mimicking multiple gut hormones. Unapproved pharmacotherapies are tempting for some patients. Others remain optimistic about more conventional routes to pharmacotherapy.3

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Section: Brown Adipose Tissuementioning

confidence: 99%

Horizons in the Pharmacotherapy of Obesity

Arch

2015

Curr Obes Rep

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“…Also, UCP-1 levels in the monkeys increased after 2-and 4-weeks of treatment (3 mg/kg, iv, twice a day). 53 The effects are expected to be similar in humans.…”

Section: ß 3 -Adrenergic Receptor Agonistsmentioning

confidence: 99%

“…Recently, a novel human ß 3 -AR agonist, 4-(3-hexyl-ureido)-N-(4-{2-[(S)-2-hydroxy-phenoxy)-propylamino]-ethyl}-phenyl)-benzenesulfonamide (L-755507), a potent and selective partial agonist, has been shown to mediate lipolysis and increase uncoupling protein-1 and metabolic rate in rhesus monkeys. 53 L-755507 exhibited an EC 50 of 0.45 nM in Chinese hamster ovary cells expressing the human ß 3 -AR with an intrinsic activity of 52% that of isoproterenol. This drug was a thousand-fold selective for the human ß 3 -AR compared with the human ß 1 -AR (EC 50 = 580 nM, intrinsic activity = 25%), with no agonist activity on cells expressing the human ß 2 -AR.…”

Section: ß 3 -Adrenergic Receptor Agonistsmentioning

confidence: 99%

β₃-Adrenergic Receptor Agonists and Other Potential Anti-obesity Agents

Vansal¹

2004

Am J Pharm Educ

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Obesity has been measured in several ways such as skin-fold thickness, waist-to-hip circumference ratio, percent of body fat, and weight adjusted for height. The most commonly used measure of weight adjusted to height is the body mass index (BMI), which is defined as weight in kilograms divided by height in meters squared (kg/m 2 ). The BMI is highly correlated to body fat, hence it is almost universally used among epidemiologists. The BMI can be quite accurately used to estimate the body fat percentage in adults using the following equation:Body fat % = 1.2 (BMI) + 0.23 (Age) -10.8 (Gender) -5.4where gender = 1 for men and 0 for women. 1 The National Institutes of Health, the American Health Foundation, and the World Health Organization (WHO) 2 have defined healthy weight as a BMI below 25 kg/m 2 , overweight as a BMI between 25 kg/m 2 and 30 kg/m 2 , and obesity as a BMI greater than 30 kg/m 2 .According to the National Health and Nutrition Examination Survey (NHANES) 1999-2000 data, 64% of Americans are overweight or obese, compared with 56% in NHANES III (1988) and 47% in NHANES II (1976-1980. 3 Increased adiposity occurs when food intake exceeds energy expenditure. Therefore, an increase in food intake or a decrease in energy expenditure, or a combination of both could cause one to gain weight. Evolutionarily, food scarcity has led to our genetic predisposition to effectively store energy in times of food abundance. Abundantly available highcalorie foods and an accompanying sedentary lifestyle are major contributing factors to the obesity epidemic. Examination of trends over the past 6 decades in England shows no relationship between either total food intake or fat consumption and the prevalence of clinical obesity, while proxy measures of physical inactivity (television viewing and car ownership) are closely related. 4 This by no means implies that the amount and type of food intake have no bearing upon obesity, but it does imply that over a large period of time, energy expenditure seems to be the more important variable in the food intake and energy expenditure balance. There is now extensive evidence that links excessive body weight with overall mortality. The relationship between BMI and mortality is a J-shaped curve with an acceleration of mortality risk above a BMI of 30 kg/m 2 . 5 Recent evidence shows that a loss of more than 9 kg in women is associated with a 25% reduction in all causes (diabetes, cardiovascular, and cancer) of mortality and this is most marked for cancer (40%-50% reduction) and diabetes (30%-40% reduction). 6 Obesity is reaching epidemic proportions in America and rising at an alarming rate throughout the world. The morbidity of cardiovascular disease, diabetes, osteoarthritis, and some cancers increases in proportion with increased obesity. Numerous anti-obesity agents are being developed that produce effects through diverse mechanisms. This paper discusses various targets for the pharmacotherapy of obesity with special attention to ß 3 -adrenergic receptors (ß 3 -AR) in obesit...

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“…In rats, this increase is reflected in thermogenesis and weight loss due to a decrease in body lipid with no loss in muscle mass (Arch et al, 1990). Recently, it was demonstrated that chronic treatment of monkeys with selective human ␤ 3 -adrenergic receptor agonists elicits lipolysis and metabolic rate elevation (Fisher et al, 1998;Hom et al, 2001). Thus, ␤ 3 -adrenergic receptor agonists might be useful for the treatment of obesity in humans.…”

Section: Ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thmentioning

confidence: 99%

The Pharmacokinetics of a Thiazole Benzenesulfonamide β₃-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability

Stearns¹,

Miller²,

Tang³

et al. 2002

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics and oral bioavailability of (R)-N- [4-[2-[[2-hydroxy-2-(pyridin-3-yl) [4-(trifluoromethylphenyl]thiazol-2-yl]benzenesulfonamide (1), a 3-pyridyl thiazole benzenesulfonamide ␤ 3 -adrenergic receptor agonist, were investigated in rats, dogs, and monkeys. Systemic clearance was higher in rats (ϳ30 ml/min/kg) than in dogs and monkeys (both ϳ10 ml/min/kg), and oral bioavailability was 17, 27, and 4%, respectively. Since systemic clearance was 25 to 40% of hepatic blood flow in these species, hepatic extraction was expected to be low, and it was likely that oral bioavailability was limited either by absorption or a large first-pass effect in the gut. The absorption and excretion of 3 H-labeled 1 were investigated in rats, and only 28% of the administered radioactivity was orally absorbed. Subsequently, the hepatic extraction of 1 was evaluated in rats (30%) and monkeys (47%). The low oral bioavailability in rats could be explained completely by poor oral absorption and hepatic first-pass metabolism; in monkeys, oral absorption was either less than in rats or first-pass extraction in the gut was greater. In an attempt to increase oral exposure, the pharmacokinetics and oral bioavailability of two potential prodrugs of 1, an N-ethyl [(R)-N-[4-[2-[ethyl[2-hydroxy-2-(3-pyridinyl) ethyl]amino]ethyl]phenyl]-4-[4- ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide; 2] and a morpholine derivative [(R)-N-[4-[2-[2-(3-pyridinyl)morpholin-4-yl]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)-phenyl]thiazol-2-yl]benzenesulfonamide; 3], were evaluated in monkeys. Conversion to 1 was low (Ͻ3%) with both derivatives, and neither entity was an effective prodrug, but the oral bioavailability of 3 (56%) compared with 1 (4%) was significantly improved. The hypothesis that the increased oral bioavailability of 3 was due to a reduction in hydrogen bonding sites in the molecule led to the design of (R) The prevalence of obesity is increasing throughout the world and especially in the United States (Kuczmarski et al., 1994, Wickelgren, 1998. This health risk is associated with the onset of other conditions such as noninsulin-dependent diabetes and cardiovascular disease (Pi-Sunyer, 1993). Basically, obesity is the result of an imbalance between caloric intake and energy expenditure. The challenge of reducing caloric intake in an obese population has led to a focus on pharmaceutical intervention to achieve weight loss. A number of therapeutic strategies have been explored for the pharmacological treatment of obesity (Kordik and Reitz, 1999). One potential mechanism for increasing energy expenditure is via activation of a unique ␤-adrenergic receptor subtype, the ␤ 3 -adrenergic receptor (Arch and Wilson, 1996;Dow, 1997;Weber, 1998). This receptor has been identified on the surface of rat adipocytes, and its activation results in the stimulation of lipolysis (Arch et al., 1984). In brown adipose tissue, ␤ 3 -adrenergic receptor activation leads to up-regulation of UCP1, a mitochondria...

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A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys.

Cited by 111 publications

References 24 publications

Horizons in the Pharmacotherapy of Obesity

Horizons in the Pharmacotherapy of Obesity

β₃-Adrenergic Receptor Agonists and Other Potential Anti-obesity Agents

The Pharmacokinetics of a Thiazole Benzenesulfonamide β₃-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability

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A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys.

Cited by 111 publications

References 24 publications

Horizons in the Pharmacotherapy of Obesity

Horizons in the Pharmacotherapy of Obesity

β3-Adrenergic Receptor Agonists and Other Potential Anti-obesity Agents

The Pharmacokinetics of a Thiazole Benzenesulfonamide β3-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability

Contact Info

Product

Resources

About

β₃-Adrenergic Receptor Agonists and Other Potential Anti-obesity Agents

The Pharmacokinetics of a Thiazole Benzenesulfonamide β₃-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability