Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a “Bio-Oxidizable” Prodrug Strategy: Design, Synthesis, and in Vitro Biological Evaluation
With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer’s disease, we report herein a new class of donepezil-based “bio-oxidizable” prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived...
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| Veröffentlicht in: | Journal of medicinal chemistry 2017-07, Vol.60 (13), p.5909-5926 |
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| container_title | Journal of medicinal chemistry |
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| creator | Peauger, Ludovic Azzouz, Rabah Gembus, Vincent Ţînţaş, Mihaela-Liliana Sopková-de Oliveira Santos, Jana Bohn, Pierre Papamicaël, Cyril Levacher, Vincent |
| description | With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer’s disease, we report herein a new class of donepezil-based “bio-oxidizable” prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the standard drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high in vitro antioxidant activity, its conversion to AChEI 2r could be easily achieved under mild conditions when incubated in various oxidizing media. Lastly, both compounds 1r and 2r did not show genotoxicity in vitro and displayed high LD50 values in mice, making this prodrug 1r/drug 2r couple a good candidate for further in vivo biological experiments. |
| doi_str_mv | 10.1021/acs.jmedchem.7b00702 |
| format | Article |
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While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the standard drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high in vitro antioxidant activity, its conversion to AChEI 2r could be easily achieved under mild conditions when incubated in various oxidizing media. 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Med. Chem</addtitle><description>With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer’s disease, we report herein a new class of donepezil-based “bio-oxidizable” prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the standard drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high in vitro antioxidant activity, its conversion to AChEI 2r could be easily achieved under mild conditions when incubated in various oxidizing media. Lastly, both compounds 1r and 2r did not show genotoxicity in vitro and displayed high LD50 values in mice, making this prodrug 1r/drug 2r couple a good candidate for further in vivo biological experiments.</description><subject>Acetylcholinesterase - metabolism</subject><subject>Alzheimer Disease - drug therapy</subject><subject>Amyloid - antagonists & inhibitors</subject><subject>Amyloid - metabolism</subject><subject>Animals</subject><subject>Chemical Sciences</subject><subject>Cholinesterase Inhibitors - chemistry</subject><subject>Cholinesterase Inhibitors - pharmacokinetics</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Donepezil</subject><subject>Drug Design</subject><subject>Female</subject><subject>Humans</subject><subject>Indans - chemistry</subject><subject>Indans - pharmacokinetics</subject><subject>Indans - pharmacology</subject><subject>Medicinal Chemistry</subject><subject>Mice</subject><subject>Molecular Docking Simulation</subject><subject>Piperidines - chemistry</subject><subject>Piperidines - pharmacokinetics</subject><subject>Piperidines - pharmacology</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacokinetics</subject><subject>Prodrugs - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAUhSMEokPhDRDyEqRmuLbzy246LbTSoCIV2FpOfDNx5bEHO6lIV30Q2PBofRJcZtolK1_5fucc6Z4keU1hToHR97IN86sNqrbHzbxsAEpgT5IZzRmkWQXZ02QGwFjKCsYPkhchXAEAp4w_Tw5YVVBe5fUs-XPiLG7xRpv0WAZUZIl28NKQRYvDZNreGW0xDOjjlpzbXjd6cD6QZiKfUdpAXEckubv9daxdevFTK30jG4N3t7_JF--UH9fkMhoOuJ4-kBMMem2PyOVkhz7O4YhIq4i25LsevCPRw7i1bmP-6bU0oxy0sy-TZ500AV_t38Pk28fTr8uzdHXx6Xy5WKUyy6ohZXUONagiz1heMqwkdJlCirJsGqZKVnDgHHmRY8cbWimasZK2slRtXeRccn6YvNv59tKIrdcb6SfhpBZni5W4_wMGGS9ZfU0j-3bHbr37Mcb7iI0OLRojLboxCFrTmJbXZR3RbIe23oXgsXv0piDumxSxSfHQpNg3GWVv9gljE3ePoofqIgA74J_cjd7G4_zf8y-1SrBN</recordid><startdate>20170713</startdate><enddate>20170713</enddate><creator>Peauger, Ludovic</creator><creator>Azzouz, Rabah</creator><creator>Gembus, Vincent</creator><creator>Ţînţaş, Mihaela-Liliana</creator><creator>Sopková-de Oliveira Santos, Jana</creator><creator>Bohn, Pierre</creator><creator>Papamicaël, Cyril</creator><creator>Levacher, Vincent</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-6429-1965</orcidid><orcidid>https://orcid.org/0000-0002-4829-8120</orcidid><orcidid>https://orcid.org/0000-0001-8972-9022</orcidid><orcidid>https://orcid.org/0000-0001-6884-6844</orcidid></search><sort><creationdate>20170713</creationdate><title>Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a “Bio-Oxidizable” Prodrug Strategy: Design, Synthesis, and in Vitro Biological Evaluation</title><author>Peauger, Ludovic ; Azzouz, Rabah ; Gembus, Vincent ; Ţînţaş, Mihaela-Liliana ; Sopková-de Oliveira Santos, Jana ; Bohn, Pierre ; Papamicaël, Cyril ; Levacher, Vincent</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a448t-295090d6542572e8a0f4de1ea7bb2d7263033e365ef3b18d14271ca7dc9653a33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Acetylcholinesterase - metabolism</topic><topic>Alzheimer Disease - drug therapy</topic><topic>Amyloid - antagonists & inhibitors</topic><topic>Amyloid - metabolism</topic><topic>Animals</topic><topic>Chemical Sciences</topic><topic>Cholinesterase Inhibitors - chemistry</topic><topic>Cholinesterase Inhibitors - pharmacokinetics</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>Donepezil</topic><topic>Drug Design</topic><topic>Female</topic><topic>Humans</topic><topic>Indans - chemistry</topic><topic>Indans - pharmacokinetics</topic><topic>Indans - pharmacology</topic><topic>Medicinal Chemistry</topic><topic>Mice</topic><topic>Molecular Docking Simulation</topic><topic>Piperidines - chemistry</topic><topic>Piperidines - pharmacokinetics</topic><topic>Piperidines - pharmacology</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - pharmacokinetics</topic><topic>Prodrugs - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Peauger, Ludovic</creatorcontrib><creatorcontrib>Azzouz, Rabah</creatorcontrib><creatorcontrib>Gembus, Vincent</creatorcontrib><creatorcontrib>Ţînţaş, Mihaela-Liliana</creatorcontrib><creatorcontrib>Sopková-de Oliveira Santos, Jana</creatorcontrib><creatorcontrib>Bohn, Pierre</creatorcontrib><creatorcontrib>Papamicaël, Cyril</creatorcontrib><creatorcontrib>Levacher, Vincent</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Peauger, Ludovic</au><au>Azzouz, Rabah</au><au>Gembus, Vincent</au><au>Ţînţaş, Mihaela-Liliana</au><au>Sopková-de Oliveira Santos, Jana</au><au>Bohn, Pierre</au><au>Papamicaël, Cyril</au><au>Levacher, Vincent</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a “Bio-Oxidizable” Prodrug Strategy: Design, Synthesis, and in Vitro Biological Evaluation</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2017-07-13</date><risdate>2017</risdate><volume>60</volume><issue>13</issue><spage>5909</spage><epage>5926</epage><pages>5909-5926</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer’s disease, we report herein a new class of donepezil-based “bio-oxidizable” prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the standard drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high in vitro antioxidant activity, its conversion to AChEI 2r could be easily achieved under mild conditions when incubated in various oxidizing media. Lastly, both compounds 1r and 2r did not show genotoxicity in vitro and displayed high LD50 values in mice, making this prodrug 1r/drug 2r couple a good candidate for further in vivo biological experiments.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>28613859</pmid><doi>10.1021/acs.jmedchem.7b00702</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-6429-1965</orcidid><orcidid>https://orcid.org/0000-0002-4829-8120</orcidid><orcidid>https://orcid.org/0000-0001-8972-9022</orcidid><orcidid>https://orcid.org/0000-0001-6884-6844</orcidid></addata></record> |
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| subjects | Acetylcholinesterase - metabolism Alzheimer Disease - drug therapy Amyloid - antagonists & inhibitors Amyloid - metabolism Animals Chemical Sciences Cholinesterase Inhibitors - chemistry Cholinesterase Inhibitors - pharmacokinetics Cholinesterase Inhibitors - pharmacology Donepezil Drug Design Female Humans Indans - chemistry Indans - pharmacokinetics Indans - pharmacology Medicinal Chemistry Mice Molecular Docking Simulation Piperidines - chemistry Piperidines - pharmacokinetics Piperidines - pharmacology Prodrugs - chemistry Prodrugs - pharmacokinetics Prodrugs - pharmacology |
| title | Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a “Bio-Oxidizable” Prodrug Strategy: Design, Synthesis, and in Vitro Biological Evaluation |
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