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Sulindac derivatives that activate the peroxisome proliferator-activated receptor gamma but lack cyclooxygenase inhibition.

Felts AS, Siegel BS, Young SM, Moth CW, Lybrand TP, Dannenberg AJ, Marnett LJ, Subbaramaiah K - J. Med. Chem. (2008)

Bottom Line: Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity.Compound 24 also stimulated the binding of PPARgamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARgamma target genes.Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

ABSTRACT
A series of novel derivatives of the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide were synthesized as potential agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity. Compound 24 was as potent a compound as any other in the series with an EC50 of 0.1 microM for the induction of peroxisome proliferator response element (PPRE)-luciferase activity. Direct binding of compound 24 to PPARgamma was demonstrated by the displacement of [(3)H]troglitazone, a PPARgamma agonist, in a scintillation proximity assay. Compound 24 also stimulated the binding of PPARgamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARgamma target genes. Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists.

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Structures of sulindac sulfide and 2.
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fig1: Structures of sulindac sulfide and 2.

Mentions: Previous studies found that a variety of nonsteroidal anti-inflammatory drugs (NSAIDs) activate PPARs at micromolar concentrations.11–13 However, the effects of NSAIDs were heterogeneous. For example, ibuprofen was demonstrated to be a coactivator of PPARα and γ, while aspirin, acetaminophen, and piroxicam showed no agonistic activity for any PPAR subtype.(13) Indomethacin and diclofenac were shown to be selective for PPARγ although certain reports have claimed that indomethacin can also act as an agonist for PPARα.(12) These compounds are attractive targets for redesign because their pharmacokinetics have already been extensively studied in humans. Chemical removal of cyclooxygenase (COX) inhibition could reduce potential gastrointestinal and cardiovascular side effects and provide excellent tools for evaluating the contribution of COX to their overall biological effects. Previous work in our laboratory has shown that a subtle chemical modification of sulindac sulfide (i.e., removal of the indenyl methyl group) abolishes inhibition of cyclooxygenase while retaining activity at other targets including PPARγ (Figure 1).(14)


Sulindac derivatives that activate the peroxisome proliferator-activated receptor gamma but lack cyclooxygenase inhibition.

Felts AS, Siegel BS, Young SM, Moth CW, Lybrand TP, Dannenberg AJ, Marnett LJ, Subbaramaiah K - J. Med. Chem. (2008)

Structures of sulindac sulfide and 2.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651753&req=5

fig1: Structures of sulindac sulfide and 2.
Mentions: Previous studies found that a variety of nonsteroidal anti-inflammatory drugs (NSAIDs) activate PPARs at micromolar concentrations.11–13 However, the effects of NSAIDs were heterogeneous. For example, ibuprofen was demonstrated to be a coactivator of PPARα and γ, while aspirin, acetaminophen, and piroxicam showed no agonistic activity for any PPAR subtype.(13) Indomethacin and diclofenac were shown to be selective for PPARγ although certain reports have claimed that indomethacin can also act as an agonist for PPARα.(12) These compounds are attractive targets for redesign because their pharmacokinetics have already been extensively studied in humans. Chemical removal of cyclooxygenase (COX) inhibition could reduce potential gastrointestinal and cardiovascular side effects and provide excellent tools for evaluating the contribution of COX to their overall biological effects. Previous work in our laboratory has shown that a subtle chemical modification of sulindac sulfide (i.e., removal of the indenyl methyl group) abolishes inhibition of cyclooxygenase while retaining activity at other targets including PPARγ (Figure 1).(14)

Bottom Line: Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity.Compound 24 also stimulated the binding of PPARgamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARgamma target genes.Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

ABSTRACT
A series of novel derivatives of the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide were synthesized as potential agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity. Compound 24 was as potent a compound as any other in the series with an EC50 of 0.1 microM for the induction of peroxisome proliferator response element (PPRE)-luciferase activity. Direct binding of compound 24 to PPARgamma was demonstrated by the displacement of [(3)H]troglitazone, a PPARgamma agonist, in a scintillation proximity assay. Compound 24 also stimulated the binding of PPARgamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARgamma target genes. Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists.

Show MeSH