Small lipidated anti-obesity compounds derived from neuromedin U

A small library of truncated/lipid-conjugated neuromedin U (NmU) analogs was synthesized and tested in vitro using an intracellular calcium signaling assay. The selected, most active analogs were then tested in vivo, and showed potent anorexigenic effects in a diet-induced obese (DIO) mouse model. T...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2015-08, Vol.101, p.616-626
Main Authors: Micewicz, Ewa D., Bahattab, Omar S.O., Willars, Gary B., Waring, Alan J., Navab, Mohamad, Whitelegge, Julian P., McBride, William H., Ruchala, Piotr
Format: Article
Language:English
Subjects:
Animals
Anti-Obesity Agents - chemical synthesis
Anti-Obesity Agents - chemistry
Anti-Obesity Agents - pharmacology
Antiobesity agents
Calcium - metabolism
Dietary Fats - adverse effects
Disease Models, Animal
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Lipid-conjugated peptides
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Neuromedin U receptor agonists
Neuropeptides - chemistry
Neuropeptides - pharmacology
Obesity
Obesity - drug therapy
Obesity - metabolism
Signal Transduction
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Structure-Activity Relationship
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Summary:A small library of truncated/lipid-conjugated neuromedin U (NmU) analogs was synthesized and tested in vitro using an intracellular calcium signaling assay. The selected, most active analogs were then tested in vivo, and showed potent anorexigenic effects in a diet-induced obese (DIO) mouse model. The most promising compound, NM4-C16 was effective in a once-weekly-dose regimen. Collectively, our findings suggest that short, lipidated analogs of NmU are suitable leads for the development of novel anti-obesity therapeutics. [Display omitted] •Truncated analogs of neuromedin U are active in vivo.•Lipidated derivatives of NmU are viable drug candidates for obesity treatment.•Position of lipidation influences affinity of NmU derivatives to NMU1 and NMU2 receptors.•The pharmacokinetic properties of selected lipidated NmU derivatives were studied in murine model.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2015.07.020