Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease
The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a vari...
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| Veröffentlicht in: | European journal of medicinal chemistry 2017-01, Vol.126, p.1-6 |
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| creator | Cheng, Wei-Chieh Wang, Jen-Hon Yun, Wen-Yi Li, Huang-Yi Hu, Jia-Ming |
| description | The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells.
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•New pyrrolidine-based pharmacological chaperones for Fabry disease are developed.•Compound 8 is a potent and selective pharmacological chaperone for Fabry disease.•It is a durable and non-substrate competitive pharmacological chaperone. |
| doi_str_mv | 10.1016/j.ejmech.2016.10.004 |
| format | Article |
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•New pyrrolidine-based pharmacological chaperones for Fabry disease are developed.•Compound 8 is a potent and selective pharmacological chaperone for Fabry disease.•It is a durable and non-substrate competitive pharmacological chaperone.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2016.10.004</identifier><identifier>PMID: 27744182</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>alpha-Galactosidase - antagonists & inhibitors ; alpha-Galactosidase - genetics ; Animals ; Azasugar ; Cercopithecus aethiops ; Combinatorial chemistry ; COS Cells ; Drug Design ; Drug Stability ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Fabry disease ; Fabry Disease - drug therapy ; Humans ; Hydroxylation ; Kinetics ; Lysosomal α-galactosidase ; Mutation ; Pharmacological chaperone ; Polyhydroxylated pyrrolidine ; Pyrrolidines - chemical synthesis ; Pyrrolidines - chemistry ; Pyrrolidines - pharmacology ; Pyrrolidines - therapeutic use ; Small Molecule Libraries - chemical synthesis ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; Small Molecule Libraries - therapeutic use ; Stereoisomerism ; Temperature</subject><ispartof>European journal of medicinal chemistry, 2017-01, Vol.126, p.1-6</ispartof><rights>2016 Elsevier Masson SAS</rights><rights>Copyright © 2016 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-5707ef55526dffdc9afb3700d8fa3be6084845c905ca18f572f1d4d7d00d1c973</citedby><cites>FETCH-LOGICAL-c428t-5707ef55526dffdc9afb3700d8fa3be6084845c905ca18f572f1d4d7d00d1c973</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2016.10.004$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,778,782,3539,27911,27912,45982</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27744182$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheng, Wei-Chieh</creatorcontrib><creatorcontrib>Wang, Jen-Hon</creatorcontrib><creatorcontrib>Yun, Wen-Yi</creatorcontrib><creatorcontrib>Li, Huang-Yi</creatorcontrib><creatorcontrib>Hu, Jia-Ming</creatorcontrib><title>Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells.
[Display omitted]
•New pyrrolidine-based pharmacological chaperones for Fabry disease are developed.•Compound 8 is a potent and selective pharmacological chaperone for Fabry disease.•It is a durable and non-substrate competitive pharmacological chaperone.</description><subject>alpha-Galactosidase - antagonists & inhibitors</subject><subject>alpha-Galactosidase - genetics</subject><subject>Animals</subject><subject>Azasugar</subject><subject>Cercopithecus aethiops</subject><subject>Combinatorial chemistry</subject><subject>COS Cells</subject><subject>Drug Design</subject><subject>Drug Stability</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Fabry disease</subject><subject>Fabry Disease - drug therapy</subject><subject>Humans</subject><subject>Hydroxylation</subject><subject>Kinetics</subject><subject>Lysosomal α-galactosidase</subject><subject>Mutation</subject><subject>Pharmacological chaperone</subject><subject>Polyhydroxylated pyrrolidine</subject><subject>Pyrrolidines - chemical synthesis</subject><subject>Pyrrolidines - chemistry</subject><subject>Pyrrolidines - pharmacology</subject><subject>Pyrrolidines - therapeutic use</subject><subject>Small Molecule Libraries - chemical synthesis</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Small Molecule Libraries - therapeutic use</subject><subject>Stereoisomerism</subject><subject>Temperature</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kVGL1DAUhYMo7rj6D0TyuMJ2TNKk7bwIy-KqsCCM-hzS5MbJ0Db1JrPY3-EfNmVWH30KOXznnuQeQl5ztuWMN--OWziOYA9bUW5F2jImn5ANb5uuqoWST8mGCVFXStTygrxI6cgYUw1jz8mFaFspeSc25PfezMHRGWE2aHKIE42eXtX7a_n1Wu3f0jkOy2FxGH8tg8lQ0AUxDsGFCarepKIMoUeDARLNkbqQbHwApIbOB4OjsXGIP4I1A7UHMwPGCaiPSDOCySNMeQ28Mz0uqxfKxJfkmTdDgleP5yX5fvfh2-2n6v7Lx8-3N_eVlaLLlWpZC14pJRrnvbM74_u6Zcx13tQ9NKyTnVR2x5Q1vPOqFZ476VpXEG53bX1Jrs5zZ4w_T5CyHsvjYRjMBPGUNO9qVdYk1a6g8oxajCkheD1jGA0umjO91qGP-lyHXutY1VJHsb15TDj1I7h_pr_7L8D7MwDlnw8BUCcbYLLgAoLN2sXw_4Q_D1efyg</recordid><startdate>20170127</startdate><enddate>20170127</enddate><creator>Cheng, Wei-Chieh</creator><creator>Wang, Jen-Hon</creator><creator>Yun, Wen-Yi</creator><creator>Li, Huang-Yi</creator><creator>Hu, Jia-Ming</creator><general>Elsevier Masson SAS</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></search><sort><creationdate>20170127</creationdate><title>Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease</title><author>Cheng, Wei-Chieh ; Wang, Jen-Hon ; Yun, Wen-Yi ; Li, Huang-Yi ; Hu, Jia-Ming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c428t-5707ef55526dffdc9afb3700d8fa3be6084845c905ca18f572f1d4d7d00d1c973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>alpha-Galactosidase - antagonists & inhibitors</topic><topic>alpha-Galactosidase - genetics</topic><topic>Animals</topic><topic>Azasugar</topic><topic>Cercopithecus aethiops</topic><topic>Combinatorial chemistry</topic><topic>COS Cells</topic><topic>Drug Design</topic><topic>Drug Stability</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Fabry disease</topic><topic>Fabry Disease - drug therapy</topic><topic>Humans</topic><topic>Hydroxylation</topic><topic>Kinetics</topic><topic>Lysosomal α-galactosidase</topic><topic>Mutation</topic><topic>Pharmacological chaperone</topic><topic>Polyhydroxylated pyrrolidine</topic><topic>Pyrrolidines - chemical synthesis</topic><topic>Pyrrolidines - chemistry</topic><topic>Pyrrolidines - pharmacology</topic><topic>Pyrrolidines - therapeutic use</topic><topic>Small Molecule Libraries - chemical synthesis</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Small Molecule Libraries - therapeutic use</topic><topic>Stereoisomerism</topic><topic>Temperature</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cheng, Wei-Chieh</creatorcontrib><creatorcontrib>Wang, Jen-Hon</creatorcontrib><creatorcontrib>Yun, Wen-Yi</creatorcontrib><creatorcontrib>Li, Huang-Yi</creatorcontrib><creatorcontrib>Hu, Jia-Ming</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><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cheng, Wei-Chieh</au><au>Wang, Jen-Hon</au><au>Yun, Wen-Yi</au><au>Li, Huang-Yi</au><au>Hu, Jia-Ming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2017-01-27</date><risdate>2017</risdate><volume>126</volume><spage>1</spage><epage>6</epage><pages>1-6</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells.
[Display omitted]
•New pyrrolidine-based pharmacological chaperones for Fabry disease are developed.•Compound 8 is a potent and selective pharmacological chaperone for Fabry disease.•It is a durable and non-substrate competitive pharmacological chaperone.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>27744182</pmid><doi>10.1016/j.ejmech.2016.10.004</doi><tpages>6</tpages></addata></record> |
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| subjects | alpha-Galactosidase - antagonists & inhibitors alpha-Galactosidase - genetics Animals Azasugar Cercopithecus aethiops Combinatorial chemistry COS Cells Drug Design Drug Stability Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Fabry disease Fabry Disease - drug therapy Humans Hydroxylation Kinetics Lysosomal α-galactosidase Mutation Pharmacological chaperone Polyhydroxylated pyrrolidine Pyrrolidines - chemical synthesis Pyrrolidines - chemistry Pyrrolidines - pharmacology Pyrrolidines - therapeutic use Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Small Molecule Libraries - therapeutic use Stereoisomerism Temperature |
| title | Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease |
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