Synthesis and biological evaluation of an orally active ghrelin agonist that stimulates food consumption and adiposity in rats

Lugar, Charles W.; Clay, Michael P.; Lindstrom, Terry D.; Woodson, Andrea L.; Smiley, David L.; Heiman, Mark L.; Dodge, Jeffrey A.

doi:10.1016/j.bmcl.2004.09.027

Cited by 18 publications

(16 citation statements)

References 15 publications

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“…However, there are almost no data on longer-term treatments or a more detailed metabolic profiling of such observations, including body composition measurements. The GHS-R agonist LY-444711 (27) represents an exception, since it has been analyzed for energy balance parameters other than food intake and body weight. As seen in rodent studies with other ligands (26,(52)(53)(54), weight gain after treatment with LY-444711 was due to increased fat mass with a decrease or no change in lean mass.…”

Section: Discussionmentioning

confidence: 99%

Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

Strassburg¹,

Anker²,

Castañeda³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol x kg(-1) x day(-1) using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.

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Section: Discussionmentioning

confidence: 99%

Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

Strassburg¹,

Anker²,

Castañeda³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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“…See ref. [169] Mice: active po [187] Rats: active iv, po; F po 10 % [169] Dogs: active po; F po 37 % [169] Agonist: ↑ GH [169] ↑ food intake, body weight [169] Chemical structures can be found in references given in brackets ACTH, cortisol and prolactin at doses higher than 3 mg/kg bw were observed [99]. Tabimorelin is a promising candidate for oral treatment of GH deficiency.…”

Section: Ly-444711mentioning

confidence: 99%

“…A similar pseudotripeptide, LY444711, was developed by Eli Lilly for the potential treatment of growth disorders. LY444711 is one of the first agonists that has been characterized for its adipogenic properties [169]. It increases food intake, body weight, and carbohydrate utilization [169], but unlike many GH secretagogues, it does not affect cortisol levels [170].…”

mentioning

confidence: 99%

Ghrelin Receptor Ligands Reaching Clinical Trials: From Peptides to Peptidomimetics; from Agonists to Antagonists

Vodnik¹,

Štrukelj

Lunder³

2015

Horm Metab Res

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In the recent decades, great progress has been made in the development of ghrelin receptor ligands. The discovery of the first in vitro only active peptide growth hormone secretagogue derived from Met-enkephalin was the foundation for later discoveries of the receptor and the endogenous ligand ghrelin. Since then, the scope of peptides, peptidomimetics, and small-molecules targeting the ghrelin receptor, GHS-R1a, has expanded dramatically. Numerous agonists have been tested in animals and several in humans, and a handful have progressed to clinical trials for indications such as growth hormone release, gastric emptying, and cachexia. However, with the exception of the approval of GHRP-2 for diagnostic purposes in Japan, none of the candidates have been successfully introduced into the market. More recently, the attention of researchers has been concentrated on developing antagonists and inverse agonists for pharmacological treatment of the ever-expanding obese and overweight population. In this review, we describe the development of GHS-R1a targeting agonists, antagonists, and inverse agonists. We focus on current and completed clinical trials and the therapeutic potential of currently available ligands.

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“…Cleavage of the methyl Table 1. Placing a hydroxy group at 8-position (5) reduced binding potency while a hydrophobic methoxy group at the same position moderately improved the activity (6). A larger ethoxy group further increased potency (7), but a propoxy group (8) seemed too bulky implying the groups at this position interact with a small hydrophobic binding pocket on the receptor.…”

mentioning

confidence: 96%

“…5 An orally active nonpeptidyl GHS-R agonist that stimulates food consumption and adiposity in rats was reported recently. 6 A small molecule GHS-R antagonist is expected to suppress food intake and reduce body weight.…”

mentioning

confidence: 99%

Structure–activity relationship studies on tetralin carboxamide growth hormone secretagogue receptor antagonists

Zhao

Xin

Patel

et al. 2005

Bioorganic & Medicinal Chemistry Letters

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Synthesis and biological evaluation of an orally active ghrelin agonist that stimulates food consumption and adiposity in rats

Cited by 18 publications

References 15 publications

Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

Ghrelin Receptor Ligands Reaching Clinical Trials: From Peptides to Peptidomimetics; from Agonists to Antagonists

Structure–activity relationship studies on tetralin carboxamide growth hormone secretagogue receptor antagonists

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