Entwicklung neuer selektiver inverser Agonisten für PPARβ/δ

Ausgehend von einem Screening mit zehn Hits wurde eine neue Grundstruktur für inverse PPARβ/δ-Agonisten identifiziert. Anhand einer auf diesem Grundgerüst basierenden systematischen Struktur-Aktivitäts-Studie mit über 80 synthetisierten Verbindungen wurden mehrere funktionelle Merkmale identifizi...

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Bibliographic Details
Main Author: Scheer, Frithjof
Contributors: Diederich, Wiebke (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2013
Online Access:PDF Full Text
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Starting from a screening with ten hits, a new core structure for inverse PPARβ/δ agonists has been identified. A structure-activity-relationship study based on this core structure with more than 80 synthesized compounds revealed several key features essential for the affinity to PPARβ/δ. By combination of these features a new selective PPARβ/δ inverse agonist has been developed, which is highly active based on the IC50 value of 9.5 nM. In addition this ligand has an oral bioavailability of 72 % with a half-life time of 10 h and is thus the first published PPARβ/δ inverse agonist suitable for the use in animal models. To identifiy the binding mode of this new ligand two strategies were pursued: protein crystallisation and photoaffinity labeling. For this purpose the ligand binding domain of PPARβ/δ was expressed in E. coli and purified to obtain sufficient amounts of protein. At the same time a photoaffinity ligand with PPARβ/δ affinity was designed and sythesized, to determine the binding position of this ligand. However, due to the prompt aggregation of the protein none of these approaches led to any insight into the binding mode.