2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats

Pan, Kevin; Scott, Mark J.; Lee, Daniel H. S.; Fitzpatrick, Louis J; Crooke, Jeffery J; Rivero, Ralph A.; Rosenthal, Daniel I.; Vaidya, Anil H.; Zhao, Boyu; Reitz, Allen B.

doi:10.1016/s0968-0896(02)00428-5

Cited by 59 publications

(24 citation statements)

References 32 publications

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“…JNJ-10229570 and JNJ-7818369 ( Fig. 1C) [24] were synthesized at Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA. For in vitro studies the compounds (1 mM) were dissolved in DMSO and were further diluted in culture media. In our experimental system DMSO (up to 0.1%) had no effect on either cytotoxicity or on sebaceous lipid production.…”

Section: Reagentsmentioning

confidence: 99%

A melanocortin receptor 1 and 5 antagonist inhibits sebaceous gland differentiation and the production of sebum-specific lipids

Eisinger

Anthonavage

et al. 2011

Journal of Dermatological Science

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Section: Reagentsmentioning

confidence: 99%

A melanocortin receptor 1 and 5 antagonist inhibits sebaceous gland differentiation and the production of sebum-specific lipids

Eisinger

Anthonavage

et al. 2011

Journal of Dermatological Science

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“…12). This compound was reported [115] to be an MC4 receptor agonist (IC 50 = 22 nM) but its agonist potency and selectivity profile were not disclosed. Compound 37 was able to significantly reduce food intake in fasted rats when administered intraperitoneally (ip) but was not effective when dosed orally.…”

Section: Melanocortin-4 (Mc4) Receptor Agonistsmentioning

confidence: 98%

Antiobesity Therapy: Emerging Drugs and Targets

Das

Chakrabarti²

2006

CMC

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Obesity and its associated morbidities and mortalities are the effects of imbalance between energy intake and expenditure. The healthcare burden for the treatment of obesity is significantly high, due to increased risk of secondary chronic diseases such as hypertension and associated co-morbidities such as diabetes and cardiovascular disease. Lack of physical activity, high fat diets and sedentary life styles are major factors contributing to obesity. However, genetic predisposition and ethnicity are increasingly found to cause obesity. Till date, approved therapeutics have addressed excess energy intake by acting on central neural circuits that regulate feeding or on peripheral mechanisms to reduce nutrient absorption from the gut. These approaches have met with moderate success; and recently with safety concerns, leaving an unmet medical need for effective and safe pharmacotherapy for obesity thereby posing a significant challenge to pharmaceutical industry. Potential antiobesity drugs, which are being investigated by different companies, can be classified in 4 broad categories: 1) Agents that primarily decrease appetite through central action; 2) Agents that primarily increase metabolic rate or affect metabolism through peripheral action; 3) Agents that act on gastrointestinal tract; and 4) Agents that not only affect obesity but also overall Metabolic Syndrome. The current review will deal mainly with different molecules, which are under development for the above-mentioned targets and also their potential benefits and disadvantages.

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“…Interesting examples of non peptide MC4R agonists have been reported by workers at Glaxo (27)(28) [94,95] and Johnson and Johnson (29) [96]. Compound 27 is a guanidine-substituted quinazolinone and the substitution pattern is suggestive of some type of -turn mimic.…”

Section: Small Molecules Hemi-peptides and Non-peptidesmentioning

confidence: 99%

“…Compound 27 is a guanidine-substituted quinazolinone and the substitution pattern is suggestive of some type of -turn mimic. Compound 29, with no amide bonds represents the farthest departure from a peptide [96]. Experimental descriptions included in the patent application indicate that activity for the series described may be present in mouse models of obesity and compound 27 is reported to have both plasma and brain exposure after oral administration.…”

Section: Small Molecules Hemi-peptides and Non-peptidesmentioning

confidence: 99%

Melanocortin - 4 Receptor Agonists for the Treatment of Obesity

Fisher¹,

Yan²,

Mayer

et al. 2007

CTMC

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The melanocortin family of receptors (MC 1-5R) and their endogenous peptide ligands (alpha, beta, gamma- MSH and ACTH) have been implicated in the control of a wide variety of behavioral and physiological functions including the homeostatic control of food intake and body weight. In rodent models, melanocortin agonists including the nonselective peptide MTII have been shown to decrease food intake and body weight while antagonists such as SHU9119 and AGRP have been shown to stimulate food intake and increase body weight. Deletion of either the MC3R or MC4R in mice was found to be associated with obesity although hyperphagia was only observed in the MC4R deficient mice. Similarly in humans, inactivating mutations of the MC4R have been found in as many as six percent of obese individuals. The suggestion from these findings that activation of MC4Rs would have an anorectic effect in humans has resulted in efforts to produce selective agonists for the treatment of obesity. Over the past decade, efforts to develop MC4R selective small molecule and peptide agonists have been met with fractional success. Many small molecule agonists have been identified; however, few have been shown to have activity in vivo. While their use as therapeutics may have limitations, selective and potent peptide agonists have been shown by several investigators to decrease food intake and body weight in rodent models. The subject of the current review is to examine the progress made to date on producing both small molecule and peptide MC4R agonists as potential therapeutics for obesity.

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2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats

Cited by 59 publications

References 32 publications

A melanocortin receptor 1 and 5 antagonist inhibits sebaceous gland differentiation and the production of sebum-specific lipids

A melanocortin receptor 1 and 5 antagonist inhibits sebaceous gland differentiation and the production of sebum-specific lipids

Antiobesity Therapy: Emerging Drugs and Targets

Melanocortin - 4 Receptor Agonists for the Treatment of Obesity

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