Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers : Understanding and improving key determinants of pharmacological properties
Copyright © 2016 Elsevier Ltd. All rights reserved..
Several isoxazole-containing series of FXR agonists have been published over the last 15years, subsequent to the prototypical amphiphilic 'hammerhead'-type structure that was originally laid out by GW4064, the first potent synthetic FXR agonist. A set of novel compounds where the hammerhead is connected to the terminal carboxylic acid-bearing aryl or heteroaryl moiety by either a cyclopropyl, a hydroxycyclobutyl or a hydroxyazetidinyl linker was synthesized in order to improve upon the ADME properties of such isoxazoles. The resulting compounds all demonstrated high potencies at the target receptor FXR but with considerable differences in their physicochemical and in vivo profiles. The structure-activity relationships for key chemical features that have a major impact on the in vivo pharmacology of this series are discussed.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:26 |
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| Enthalten in: |
Bioorganic & medicinal chemistry letters - 26(2016), 15 vom: 01. Aug., Seite 3746-53 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kinzel, Olaf [VerfasserIn] |
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| Links: |
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| Themen: |
0C5V0MRU6P |
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| Anmerkungen: |
Date Completed 20.06.2017 Date Revised 02.12.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmcl.2016.05.070 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2016 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Several isoxazole-containing series of FXR agonists have been published over the last 15years, subsequent to the prototypical amphiphilic 'hammerhead'-type structure that was originally laid out by GW4064, the first potent synthetic FXR agonist. A set of novel compounds where the hammerhead is connected to the terminal carboxylic acid-bearing aryl or heteroaryl moiety by either a cyclopropyl, a hydroxycyclobutyl or a hydroxyazetidinyl linker was synthesized in order to improve upon the ADME properties of such isoxazoles. The resulting compounds all demonstrated high potencies at the target receptor FXR but with considerable differences in their physicochemical and in vivo profiles. The structure-activity relationships for key chemical features that have a major impact on the in vivo pharmacology of this series are discussed | ||
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| 700 | 1 | |a Gege, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Hahn, Ulrike |e verfasserin |4 aut | |
| 700 | 1 | |a Hambruch, Eva |e verfasserin |4 aut | |
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| 700 | 1 | |a Spalwisz, Adriana |e verfasserin |4 aut | |
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| 700 | 1 | |a Perović-Ottstadt, Sanja |e verfasserin |4 aut | |
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| 700 | 1 | |a Burnet, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Kremoser, Claus |e verfasserin |4 aut | |
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