Abstract
To overcome the known liabilities of GW4064 a series of analogs were synthesized where the stilbene double bond is replaced by an oxymethylene or amino-methylene linker connecting a terminal benzoic acid with a substituted heteroaryl in the middle ring position. As a result we discovered compounds with increased potency in vitro that cause dose-dependent reduction of plasma triglycerides and cholesterol in db/db mice down to 2 x 1 mg/kg/day upon oral administration.
2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Anti-Obesity Agents / chemical synthesis*
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Anti-Obesity Agents / chemistry
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Anti-Obesity Agents / pharmacology
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Binding Sites
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Cholesterol / blood
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Computer Simulation
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Isoxazoles / chemical synthesis
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Isoxazoles / chemistry*
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Isoxazoles / pharmacology
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Mice
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Mice, Obese
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Triglycerides / blood
Substances
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Anti-Obesity Agents
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Isoxazoles
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Receptors, Cytoplasmic and Nuclear
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Triglycerides
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farnesoid X-activated receptor
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Cholesterol
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GW 4064