Discovery, Optimization, and Biological Characterization of 2,3,6-Trisubstituted Pyridine-Containing M4 Positive Allosteric Modulators
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim..
Herein we describe the discovery and optimization of a new series of 2,3-disubstituted and 2,3,6-trisubstituted muscarinic acetylcholine receptor 4 (M4 ) positive allosteric modulators (PAMs). Iterative libraries enabled rapid exploration of one-dimensional structure-activity relationships (SAR) and identification of potency-enhancing heterocycle and N-alkyl pyrazole substituents. Further optimization led to identification of the potent, receptor-subtype-selective, brain-penetrant tool compound 24 (7-[3-[1-[(1-fluorocyclopentyl)methyl]pyrazol-4-yl]-6-methyl-2-pyridyl]-3-methoxycinnoline). It is efficacious in preclinical assays that are predictive of antipsychotic effects, producing dose-dependent reversal of amphetamine-induced hyperlocomotion in rats and mice, but not in M4 knockout mice. Cholinergic-related adverse effects observed in rats treated with 24 at unbound plasma concentrations more than 3-fold higher than an efficacious dose in the hyperlocomotion assay were fewer and less severe than those observed in rats treated with the nonselective M4 agonist xanomeline, suggesting a receptor-subtype-selective PAM has the potential for an improved safety profile.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
ChemMedChem - 14(2019), 9 vom: 06. Mai, Seite 943-951 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schubert, Jeffrey W [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Completed 17.02.2020 Date Revised 17.02.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/cmdc.201900088 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM295429542 |
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| 520 | |a © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. | ||
| 520 | |a Herein we describe the discovery and optimization of a new series of 2,3-disubstituted and 2,3,6-trisubstituted muscarinic acetylcholine receptor 4 (M4 ) positive allosteric modulators (PAMs). Iterative libraries enabled rapid exploration of one-dimensional structure-activity relationships (SAR) and identification of potency-enhancing heterocycle and N-alkyl pyrazole substituents. Further optimization led to identification of the potent, receptor-subtype-selective, brain-penetrant tool compound 24 (7-[3-[1-[(1-fluorocyclopentyl)methyl]pyrazol-4-yl]-6-methyl-2-pyridyl]-3-methoxycinnoline). It is efficacious in preclinical assays that are predictive of antipsychotic effects, producing dose-dependent reversal of amphetamine-induced hyperlocomotion in rats and mice, but not in M4 knockout mice. Cholinergic-related adverse effects observed in rats treated with 24 at unbound plasma concentrations more than 3-fold higher than an efficacious dose in the hyperlocomotion assay were fewer and less severe than those observed in rats treated with the nonselective M4 agonist xanomeline, suggesting a receptor-subtype-selective PAM has the potential for an improved safety profile | ||
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| 650 | 4 | |a positive allosteric modulator (PAM) | |
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| 700 | 1 | |a Mulhearn, James |e verfasserin |4 aut | |
| 700 | 1 | |a Gomez, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Tynebor, Robert |e verfasserin |4 aut | |
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| 700 | 1 | |a Bunda, Jaime |e verfasserin |4 aut | |
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| 700 | 1 | |a Wai, Jenny Miu-Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Cox, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a McCauley, John A |e verfasserin |4 aut | |
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