Discovery and pharmacology of the covalent GLP-1 receptor (GLP-1R) allosteric modulator BETP : A novel tool to probe GLP-1R pharmacology
© 2020 Elsevier Inc. All rights reserved..
The glucagon-like peptide-1 receptor (GLP-1R) is a significant therapeutic target for small molecule drug discovery given the therapeutic impact of peptide agonists in the diabetes sphere. We review the discovery and subsequent characterization of the small molecule GLP-1R allosteric modulator 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP). BETP is a covalent modulator of the GLP-1R, and we discuss the pharmacological implications and possible structural basis of this novel mode of action. We highlight the insights into class B G-protein coupled receptor pharmacology and biology provided by studies conducted with BETP. These include the descriptions of exquisite allosteric modulator probe dependence and biased signaling in vitro and in vivo. We conclude with an analysis of the utility of BETP as a chemical probe for the GLP-1R.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:88 |
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| Enthalten in: |
Advances in pharmacology (San Diego, Calif.) - 88(2020) vom: 23., Seite 173-191 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Willard, Francis S [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.09.2020 Date Revised 29.09.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/bs.apha.2020.02.001 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM309995175 |
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| 245 | 1 | 0 | |a Discovery and pharmacology of the covalent GLP-1 receptor (GLP-1R) allosteric modulator BETP |b A novel tool to probe GLP-1R pharmacology |
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| 500 | |a Date Revised 29.09.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 Elsevier Inc. All rights reserved. | ||
| 520 | |a The glucagon-like peptide-1 receptor (GLP-1R) is a significant therapeutic target for small molecule drug discovery given the therapeutic impact of peptide agonists in the diabetes sphere. We review the discovery and subsequent characterization of the small molecule GLP-1R allosteric modulator 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP). BETP is a covalent modulator of the GLP-1R, and we discuss the pharmacological implications and possible structural basis of this novel mode of action. We highlight the insights into class B G-protein coupled receptor pharmacology and biology provided by studies conducted with BETP. These include the descriptions of exquisite allosteric modulator probe dependence and biased signaling in vitro and in vivo. We conclude with an analysis of the utility of BETP as a chemical probe for the GLP-1R | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Review | |
| 650 | 4 | |a Agonist | |
| 650 | 4 | |a Allosteric modulator | |
| 650 | 4 | |a BETP | |
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| 650 | 4 | |a G-protein coupled receptor | |
| 650 | 4 | |a Glucagon-like peptide 1 | |
| 650 | 4 | |a Insulin | |
| 650 | 4 | |a Transmembrane helix | |
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