Prodrugs of CL316243: a selective β3-adrenergic receptor agonist for treating obesity and diabetes

Sum, Fuk‐Wah; Gilbert, Adam M.; Venkatesan, Aranapakam M.; Lim, Kitae; Wong, Victoria; O’Dell, Malikah; Francisco, Gerardo D.; Chen, Z.; Grosu, G; Baker, Jillian G.; Ellingboe, John W.; Malamas, Michael S.; Gunawan, Iwan; Primeau, John L.; Largis, Elwood; Steiner, Kurt

doi:10.1016/s0960-894x(99)00316-9

Cited by 25 publications

(10 citation statements)

References 6 publications

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“…It has long been known that BAT thermogenesis is regulated by the central nervous system through the SNS31. To test the contribution of the SNS to the activation of mTORC1, we first injected mice with CL316,243 (CL), a highly selective β3-adrenergic agonist that activates BAT thermogenesis323334. We observed that CL strongly increased mTORC1 activity in BAT (Figure S1D).…”

Section: Resultsmentioning

confidence: 99%

mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold

Labbé

Mouchiroud

Caron

et al. 2016

Sci Rep

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In response to cold, brown adipose tissue (BAT) increases its metabolic rate and expands its mass to produce heat required for survival, a process known as BAT recruitment. The mechanistic target of rapamycin complex 1 (mTORC1) controls metabolism, cell growth and proliferation, but its role in regulating BAT recruitment in response to chronic cold stimulation is unknown. Here, we show that cold activates mTORC1 in BAT, an effect that depends on the sympathetic nervous system. Adipocyte-specific mTORC1 loss in mice completely blocks cold-induced BAT expansion and severely impairs mitochondrial biogenesis. Accordingly, mTORC1 loss reduces oxygen consumption and causes a severe defect in BAT oxidative metabolism upon cold exposure. Using in vivo metabolic imaging, metabolomics and transcriptomics, we show that mTORC1 deletion impairs glucose and lipid oxidation, an effect linked to a defect in tricarboxylic acid (TCA) cycle activity. These analyses also reveal a severe defect in nucleotide synthesis in the absence of mTORC1. Overall, these findings demonstrate an essential role for mTORC1 in the regulation of BAT recruitment and metabolism in response to cold.

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Section: Resultsmentioning

confidence: 99%

mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold

Labbé

Mouchiroud

Caron

et al. 2016

Sci Rep

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“…These recent developments have led to a resurgence of research into drugs targeting β 3 receptors. Novel generation of highly selective β 3 receptor agonists have been tried in clinical trials [10, 19, 200, 201]. CL 316243 increased insulin-mediated glucose disposal and fat oxidation in human volunteers, without causing tremors and cardiac stimulation [200].…”

Section: Drugs That Increase Energy Expenditure and Increase Metabolimentioning

confidence: 99%

“…However, the poor oral bioavailability of CL316243 is a major drawback. Prodrugs with improved bioavailability have also been developed [201]. The oral bioavailability of a single dose of LY377604 was greater than 20%, and in obese sbjects it was shown to increase metabolic rate by 17.5% [10].…”

Section: Drugs That Increase Energy Expenditure and Increase Metabolimentioning

confidence: 99%

Obesity Pharmacotherapy: Current Perspectives and Future Directions

Misra

2013

CCR

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Abstract:The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis

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“…L-749372 is also a β 3 -AR partial agonist (EC 50 = 3.6 nM, 33% activation), with 270- and 30-fold selectivity over binding to β 1 - and β 2 -ARs, respectively (Naylor et al , 1998). The 4-piperidino-benzoic acid derivative CL-316243 was found to be a modestly potent human β 3 -AR agonist (EC 50 = 0.22 μM) (Sum et al , 1999), and N -(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamide (BMS-201620) a potent β 3 full agonist ( k i = 93 nM) (Washburn et al , 2004). …”

Section: Introductionmentioning

confidence: 99%

Comparative 3D QSAR study on β1-, β2-, and β3-adrenoceptor agonists

Kumar

Bharatam

2009

Med Chem Res

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A quantitative structure–activity relationship study of tryptamine-based derivatives of β1-, β2-, and β3-adrenoceptor agonists was conducted using comparative molecular field analysis (CoMFA). Correlation coefficients (cross-validated r2) of 0.578, 0.595, and 0.558 were obtained for the three subtypes, respectively, in three different CoMFA models. All three CoMFA models have different steric and electrostatic contributions, implying different requirements inside the binding cavity. The CoMFA coefficient contour plots of the three models and comparisons among these plots provide clues regarding the main chemical features responsible for the biological activity variations and also result in predictions which correlate very well with the observed biological activity. Based on the analysis, a summary regeospecific description of the requirements for improving β-adrenoceptor subtype selectivity is given.

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Prodrugs of CL316243: a selective β3-adrenergic receptor agonist for treating obesity and diabetes

Cited by 25 publications

References 6 publications

mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold

mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold

Obesity Pharmacotherapy: Current Perspectives and Future Directions

Comparative 3D QSAR study on β1-, β2-, and β3-adrenoceptor agonists

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