Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties
Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clog P) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:61 |
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| Enthalten in: |
Journal of medicinal chemistry - 61(2018), 21 vom: 08. Nov., Seite 9534-9550 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hansen, Anders Højgaard [VerfasserIn] |
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| Links: |
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| Themen: |
FFA2R protein, human |
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| Anmerkungen: |
Date Completed 19.09.2019 Date Revised 08.10.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.8b00855 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM288842537 |
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| 100 | 1 | |a Hansen, Anders Højgaard |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Completed 19.09.2019 | ||
| 500 | |a Date Revised 08.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clog P) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a FFA2R protein, human |2 NLM | |
| 650 | 7 | |a Receptors, Cell Surface |2 NLM | |
| 650 | 7 | |a Thiazolidines |2 NLM | |
| 700 | 1 | |a Sergeev, Eugenia |e verfasserin |4 aut | |
| 700 | 1 | |a Bolognini, Daniele |e verfasserin |4 aut | |
| 700 | 1 | |a Sprenger, Richard R |e verfasserin |4 aut | |
| 700 | 1 | |a Ekberg, Jeppe Hvidtfeldt |e verfasserin |4 aut | |
| 700 | 1 | |a Ejsing, Christer S |e verfasserin |4 aut | |
| 700 | 1 | |a McKenzie, Christine J |e verfasserin |4 aut | |
| 700 | 1 | |a Rexen Ulven, Elisabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Milligan, Graeme |e verfasserin |4 aut | |
| 700 | 1 | |a Ulven, Trond |e verfasserin |4 aut | |
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