Abstract
A series of amphipathic 3-phenylbenzisoxazoles were found to be potent agonists of human PPARalpha, gamma and delta. The optimization of acid proximal structure for in vitro and in vivo potency is described. Results of po dosed efficacy studies in the db/db mouse model of type 2 diabetes showed efficacy equal or superior to Rosiglitazone in correcting hyperglycemia and hypertriglyceridemia. Good functional receptor selectivity for PPARalpha and gamma over PPARdelta can be obtained.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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COS Cells
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Diabetes Mellitus, Type 2 / drug therapy
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Disease Models, Animal
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Humans
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Isoxazoles / chemistry*
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Isoxazoles / pharmacokinetics
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Isoxazoles / pharmacology*
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Mice
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Mice, Mutant Strains
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Nuclear Proteins / agonists
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Nuclear Proteins / metabolism
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Rosiglitazone
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology
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Thiazolidinediones*
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Transcription Factors / agonists*
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Transcription Factors / metabolism
Substances
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Isoxazoles
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Nuclear Proteins
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Receptors, Cytoplasmic and Nuclear
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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Rosiglitazone