Abstract
SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol (1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival in lower organisms and in mice on a high fat diet. Herein, we describe the identification and SAR of a series of oxazolo[4,5-b]pyridines as novel small molecule activators of SIRT1 which are structurally unrelated to and more potent than resveratrol.
MeSH terms
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Animals
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Humans
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Mice
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Mice, Transgenic
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Oxazoles / chemical synthesis*
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Oxazoles / metabolism*
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Oxazoles / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / metabolism*
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Pyridines / pharmacology
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Rats
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Rats, Zucker
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Sirtuin 1
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Sirtuins / agonists
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Sirtuins / metabolism*
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Structure-Activity Relationship
Substances
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Bridged Bicyclo Compounds, Heterocyclic
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Oxazoles
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Pyridines
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SIRT1 protein, human
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Sirtuin 1
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Sirtuins