Abstract
PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Administration, Oral
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Animals
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Binding Sites
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Crystallography, X-Ray
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism
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Diabetes Mellitus, Experimental / drug therapy
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Half-Life
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Insulin Resistance
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Male
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Mice
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PPAR gamma / agonists*
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PPAR gamma / metabolism
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Protein Structure, Tertiary
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Quinolines / chemistry*
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Quinolines / pharmacokinetics
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Quinolines / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Rats, Zucker
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / pharmacokinetics
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Sulfonamides / therapeutic use
Substances
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Cytochrome P-450 Enzyme Inhibitors
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INT 131
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PPAR gamma
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Quinolines
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Sulfonamides
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Cytochrome P-450 Enzyme System
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Cyp3a2 protein, rat
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Cytochrome P-450 CYP3A