Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation
Autor: | Julia Ohrndorf, Jurema Schmidt, Leonie Gellrich, Ewgenij Proschak, Daniel Merk, Simone Schierle, Jan Heering, Lena Kalinowsky, Whitney Kilu, Julius Pollinger, Astrid Kaiser |
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Přispěvatelé: | Publica |
Rok vydání: | 2019 |
Předmět: |
Agonist
Male medicine.drug_class Peroxisome Proliferator-Activated Receptors Peroxisome proliferator-activated receptor Retinoid X receptor 01 natural sciences 03 medical and health sciences Structure-Activity Relationship Drug Discovery medicine Structure–activity relationship Animals Humans Retinoid Receptor 030304 developmental biology chemistry.chemical_classification 0303 health sciences Molecular Structure Chemistry HEK 293 cells Hep G2 Cells 0104 chemical sciences Cell biology Rats body regions Mice Inbred C57BL 010404 medicinal & biomolecular chemistry HEK293 Cells Pyrimidines Retinoid X Receptors Nuclear receptor embryonic structures Microsomes Liver Molecular Medicine |
Zdroj: | Journal of medicinal chemistry. 62(4) |
ISSN: | 1520-4804 |
Popis: | The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure-activity relationship analysis with the discovery of specific molecular determinants driving activity on PPARs and RXRs. We have designed close analogues of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacological tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery. |
Databáze: | OpenAIRE |
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