Abstract
The discovery and SAR of a novel series of potent and selective PPARα antagonists are herein described. Exploration of replacements for the labile acyl sulfonamide linker led to a biaryl sulfonamide series of which compound 33 proved to be suitable for further profiling in vivo. Compound 33 demonstrated excellent potency, selectivity against other nuclear hormone receptors, and good pharmacokinetics in mouse.
Keywords:
Antagonist; Cancer; Fatty acid oxidation; Nuclear hormone receptor; PPAR alpha.
Copyright © 2014 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Butyrates / chemistry
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Butyrates / pharmacology
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Humans
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Mice
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Molecular Structure
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Oxazoles / chemistry
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Oxazoles / pharmacology
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PPAR alpha / antagonists & inhibitors*
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Phenylurea Compounds / chemistry
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Phenylurea Compounds / pharmacology
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Propionates / chemistry
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Propionates / pharmacology
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Structure-Activity Relationship
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology*
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Triazoles / chemistry
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Triazoles / pharmacology
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Tyrosine / analogs & derivatives
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Tyrosine / chemistry
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Tyrosine / pharmacology
Substances
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Butyrates
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GW 409544
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GW 7647
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LY 518674
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Oxazoles
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PPAR alpha
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Phenylurea Compounds
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Propionates
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Sulfonamides
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Triazoles
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Tyrosine