Design and Structural Optimization of Dual FXR/PPARδ Activators
| Autor: | Sabine Willems, Astrid Kaiser, Simone Schierle, Sebastian Neumann, Julius Pollinger, Daniel Merk, Pascal Heitel |
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| Rok vydání: | 2020 |
| Předmět: |
Agonist
medicine.drug_class Peroxisome proliferator-activated receptor Receptors Cytoplasmic and Nuclear Ligands 01 natural sciences 03 medical and health sciences Structure-Activity Relationship Non-alcoholic Fatty Liver Disease Drug Discovery medicine Humans PPAR delta Receptor Transcription factor 030304 developmental biology chemistry.chemical_classification 0303 health sciences Chemistry Drug discovery Activator (genetics) 0104 chemical sciences Cell biology Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Nuclear receptor Drug Design Molecular Medicine Farnesoid X receptor |
| Zdroj: | Journal of medicinal chemistry. 63(15) |
| ISSN: | 1520-4804 |
| Popis: | Nonalcoholic steatohepatitis (NASH) is considered as severe hepatic manifestation of the metabolic syndrome and has alarming global prevalence. The ligand-activated transcription factors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) δ have been validated as molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPARδ-mediated activity and hepatic effects of FXR activation appear as a promising multitarget approach. We have designed a minimal dual FXR/PPARδ activator scaffold by rational fusion of pharmacophores derived from selective agonists. Our dual agonist lead compound exhibited weak agonism on FXR and PPARδ and was structurally refined to a potent and balanced FXR/PPARδ activator in a computer-aided fashion. The resulting dual FXR/PPARδ modulator comprises high selectivity over related nuclear receptors and activates the two target transcription factors in native cellular settings. |
| Databáze: | OpenAIRE |
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