Fragment-based lead discovery of a novel class of small molecule antagonists of neuropeptide B/W receptor subtype 1 (GPR7)
Copyright © 2020 Elsevier Ltd. All rights reserved..
Here, we report the discovery of a new class of NPBWR1 antagonists identified from a fragment-based screen. Compound 1 (cAMP IC50 = 250 µM; LE = 0.29) emerged as an initial hit. Further optimization of 1 by SAR-by-catalogue and chemical modification produced 21a (cAMP IC50 = 30 nM; LE = 0.39) with a 6700-fold increase in potency from fragment 1. Somewhat surprisingly, Schild analysis of compound 21a suggested that in vitro inhibition of NPW-mediated effects on upon cAMP accumulation were saturable, and that compound 21a dose-dependently increased [125I]-hNPW23 dissociation rate constants from NPBWR1 in kinetic binding studies. Collectively, these data are inconsistent with a classic surmountable, orthosteric mechanism of inhibition. The benzimidazole inhibitors reported herein may therefore represent a mechanistically differentiated class of compounds with which to form a better appreciation of the pharmacology and physiological roles of this central neuropeptide system.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Bioorganic & medicinal chemistry letters - 30(2020), 23 vom: 01. Dez., Seite 127510 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Moningka, Remond [VerfasserIn] |
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| Links: |
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| Themen: |
Anti-obesity |
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| Anmerkungen: |
Date Completed 02.07.2021 Date Revised 02.07.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmcl.2020.127510 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM314713514 |
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| 245 | 1 | 0 | |a Fragment-based lead discovery of a novel class of small molecule antagonists of neuropeptide B/W receptor subtype 1 (GPR7) |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 Elsevier Ltd. All rights reserved. | ||
| 520 | |a Here, we report the discovery of a new class of NPBWR1 antagonists identified from a fragment-based screen. Compound 1 (cAMP IC50 = 250 µM; LE = 0.29) emerged as an initial hit. Further optimization of 1 by SAR-by-catalogue and chemical modification produced 21a (cAMP IC50 = 30 nM; LE = 0.39) with a 6700-fold increase in potency from fragment 1. Somewhat surprisingly, Schild analysis of compound 21a suggested that in vitro inhibition of NPW-mediated effects on upon cAMP accumulation were saturable, and that compound 21a dose-dependently increased [125I]-hNPW23 dissociation rate constants from NPBWR1 in kinetic binding studies. Collectively, these data are inconsistent with a classic surmountable, orthosteric mechanism of inhibition. The benzimidazole inhibitors reported herein may therefore represent a mechanistically differentiated class of compounds with which to form a better appreciation of the pharmacology and physiological roles of this central neuropeptide system | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Anti-obesity | |
| 650 | 4 | |a G protein-coupled receptor | |
| 650 | 4 | |a GPR7 | |
| 650 | 4 | |a NPBWR1 | |
| 650 | 4 | |a Schild plot analysis | |
| 650 | 7 | |a Benzimidazoles |2 NLM | |
| 650 | 7 | |a NPBWR1 protein, human |2 NLM | |
| 650 | 7 | |a Receptors, G-Protein-Coupled |2 NLM | |
| 650 | 7 | |a Receptors, Neuropeptide |2 NLM | |
| 700 | 1 | |a Romero, F Anthony |e verfasserin |4 aut | |
| 700 | 1 | |a Hastings, Nicholas B |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Zhiqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Di Salvo, Jerry |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Trusca, Dorina |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Qiaoling |e verfasserin |4 aut | |
| 700 | 1 | |a Tong, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Terebetski, Jenna L |e verfasserin |4 aut | |
| 700 | 1 | |a Ball, Richard G |e verfasserin |4 aut | |
| 700 | 1 | |a Ujjainwalla, Feroze |e verfasserin |4 aut | |
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