A Selective Modulator of Peroxisome Proliferator-Activated Receptor γ with an Unprecedented Binding Mode

The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARγ modulation are required. Here, we report the dis...

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Published inJournal of medicinal chemistry Vol. 63; no. 9; pp. 4555 - 4561
Main Authors Hanke, Thomas, Cheung, Sun-Yee, Kilu, Whitney, Heering, Jan, Ni, Xiaomin, Planz, Viktoria, Schierle, Simone, Faudone, Giuseppe, Friedrich, Marius, Wanior, Marek, Werz, Oliver, Windbergs, Maike, Proschak, Ewgenij, Schubert-Zsilavecz, Manfred, Chaikuad, Apirat, Knapp, Stefan, Merk, Daniel
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 14.05.2020
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
RISK
PIOGLITAZONE
ROSIGLITAZONE
MYOCARDIAL-INFARCTION
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Abstract The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARγ modulation are required. Here, we report the discovery and profiling of a new PPARγ modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARγ ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPARγ activation with a high eudysmic ratio. The new PPARγ modulator revealed outstanding selectivity over the PPARα and PPARδ subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.
AbstractList The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARγ modulation are required. Here, we report the discovery and profiling of a new PPARγ modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARγ ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPARγ activation with a high eudysmic ratio. The new PPARγ modulator revealed outstanding selectivity over the PPARα and PPARδ subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.
The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARγ modulation are required. Here, we report the discovery and profiling of a new PPARγ modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARγ ligand-binding site. Its -enantiomer evolved as a eutomer regarding PPARγ activation with a high eudysmic ratio. The new PPARγ modulator revealed outstanding selectivity over the PPARα and PPARδ subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.
The nuclear peroxisome proliferator-activated receptor gamma has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPAR gamma modulation are required. Here, we report the discovery and profiling of a new PPAR gamma modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPAR. ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPAR. activation with a high eudysmic ratio. The new PPAR gamma modulator revealed outstanding selectivity over the PPAR alpha and PPAR delta subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.
Author Heering, Jan
Knapp, Stefan
Kilu, Whitney
Merk, Daniel
Cheung, Sun-Yee
Schierle, Simone
Hanke, Thomas
Faudone, Giuseppe
Friedrich, Marius
Windbergs, Maike
Wanior, Marek
Planz, Viktoria
Ni, Xiaomin
Proschak, Ewgenij
Chaikuad, Apirat
Werz, Oliver
Schubert-Zsilavecz, Manfred
AuthorAffiliation Institute of Pharmaceutical Technology
Department of Pharmaceutical/Medicinal Chemistry
Fraunhofer Institute for Molecular Biology and Applied Ecology IME
Institute of Pharmaceutical Chemistry
Branch for Translational Medicine and Pharmacology TMP
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Snippet The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative...
The nuclear peroxisome proliferator-activated receptor gamma has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative...
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SubjectTerms Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
Title A Selective Modulator of Peroxisome Proliferator-Activated Receptor γ with an Unprecedented Binding Mode
URI http://dx.doi.org/10.1021/acs.jmedchem.9b01786
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