Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders
Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
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| Enthalten in: |
Journal of medicinal chemistry - 62(2019), 10 vom: 23. Mai, Seite 4884-4901 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gurney, Mark E [VerfasserIn] |
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| Links: |
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| Themen: |
Cyclic Nucleotide Phosphodiesterases, Type 4 |
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| Anmerkungen: |
Date Completed 01.06.2020 Date Revised 22.10.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.9b00193 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM296333212 |
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| 245 | 1 | 0 | |a Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders |
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| 500 | |a Date Revised 22.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Nugent, Richard A |e verfasserin |4 aut | |
| 700 | 1 | |a Mo, Xuesheng |e verfasserin |4 aut | |
| 700 | 1 | |a Sindac, Janice A |e verfasserin |4 aut | |
| 700 | 1 | |a Hagen, Timothy J |e verfasserin |4 aut | |
| 700 | 1 | |a Fox, David |c 3rd |e verfasserin |4 aut | |
| 700 | 1 | |a O'Donnell, James M |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Chong |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Han-Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Groppi, Vincent E |e verfasserin |4 aut | |
| 700 | 1 | |a Bailie, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a White, Ronald E |e verfasserin |4 aut | |
| 700 | 1 | |a Romero, Donna L |e verfasserin |4 aut | |
| 700 | 1 | |a Vellekoop, A Samuel |e verfasserin |4 aut | |
| 700 | 1 | |a Walker, Joel R |e verfasserin |4 aut | |
| 700 | 1 | |a Surman, Matthew D |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Campbell, Robert F |e verfasserin |4 aut | |
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