دورية أكاديمية
Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor γ Agonists/Soluble Epoxide Hydrolase Inhibitors.
| العنوان: | Structure-Based Design of Dual Partial Peroxisome Proliferator-Activated Receptor γ Agonists/Soluble Epoxide Hydrolase Inhibitors. |
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| المؤلفون: | Lillich FF; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Willems S; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Ni X; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University, Max-von-Laue-Str. 15, D-60438 Frankfurt, Germany., Kilu W; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Borkowsky C; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Brodsky M; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Kramer JS; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Brunst S; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Hernandez-Olmos V; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, D-60596 Frankfurt, Germany., Heering J; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, D-60596 Frankfurt, Germany., Schierle S; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Kestner RI; Department of Neurology, University Hospital Frankfurt, Goethe University, D-60590 Frankfurt am Main, Germany., Mayser FM; Department of Neurology, University Hospital Frankfurt, Goethe University, D-60590 Frankfurt am Main, Germany., Helmstädter M; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Göbel T; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Weizel L; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Namgaladze D; Institute of Biochemistry I, University Hospital Frankfurt, Goethe University, D-60590 Frankfurt am Main, Germany., Kaiser A; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Steinhilber D; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Pfeilschifter W; Department of Neurology, University Hospital Frankfurt, Goethe University, D-60590 Frankfurt am Main, Germany., Kahnt AS; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Proschak A; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Chaikuad A; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University, Max-von-Laue-Str. 15, D-60438 Frankfurt, Germany., Knapp S; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University, Max-von-Laue-Str. 15, D-60438 Frankfurt, Germany., Merk D; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany., Proschak E; Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, D-60596 Frankfurt, Germany. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2021 Dec 09; Vol. 64 (23), pp. 17259-17276. Date of Electronic Publication: 2021 Nov 24. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Drug Design*, Enzyme Inhibitors/*chemistry , Enzyme Inhibitors/*pharmacology , Epoxide Hydrolases/*antagonists & inhibitors , PPAR gamma/*agonists, Animals ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Mice ; Microsomes, Liver/drug effects ; Microsomes, Liver/metabolism ; Polypharmacy ; Rats ; Structure-Activity Relationship |
| مستخلص: | Polypharmaceutical regimens often impair treatment of patients with metabolic syndrome (MetS), a complex disease cluster, including obesity, hypertension, heart disease, and type II diabetes. Simultaneous targeting of soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptor γ (PPARγ) synergistically counteracted MetS in various in vivo models, and dual sEH inhibitors/PPARγ agonists hold great potential to reduce the problems associated with polypharmacy in the context of MetS. However, full activation of PPARγ leads to fluid retention associated with edema and weight gain, while partial PPARγ agonists do not have these drawbacks. In this study, we designed a dual partial PPARγ agonist/sEH inhibitor using a structure-guided approach. Exhaustive structure-activity relationship studies lead to the successful optimization of the designed lead. Crystal structures of one representative compound with both targets revealed potential points for optimization. The optimized compounds exhibited favorable metabolic stability, toxicity, selectivity, and desirable activity in adipocytes and macrophages. |
| المشرفين على المادة: | 0 (Enzyme Inhibitors) 0 (PPAR gamma) EC 3.3.2.- (Epoxide Hydrolases) |
| تواريخ الأحداث: | Date Created: 20211124 Date Completed: 20220121 Latest Revision: 20220121 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1021/acs.jmedchem.1c01331 |
| PMID: | 34818007 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.1c01331 |