Rational Design and Synthesis of Highly Potent Pharmacological Chaperones for Treatment of N370S Mutant Gaucher Disease
Highly potent N-substituted δ-lactams have been rationally designed and synthesized by a concise route with a one-pot tandem reaction as key step. These iminosugars show weak inhibition of wild-type β-glucocerebrosidase but 3- to 6-fold increases in mutant enzyme activity (N370S).
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| Veröffentlicht in: | Journal of medicinal chemistry 2009-05, Vol.52 (10), p.3146-3149 |
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| container_end_page | 3149 |
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| container_issue | 10 |
| container_start_page | 3146 |
| container_title | Journal of medicinal chemistry |
| container_volume | 52 |
| creator | Wang, Guan-Nan Reinkensmeier, Gabriele Zhang, Si-Wei Zhou, Jian Zhang, Liang-Ren Zhang, Li-He Butters, Terry D Ye, Xin-Shan |
| description | Highly potent N-substituted δ-lactams have been rationally designed and synthesized by a concise route with a one-pot tandem reaction as key step. These iminosugars show weak inhibition of wild-type β-glucocerebrosidase but 3- to 6-fold increases in mutant enzyme activity (N370S). |
| doi_str_mv | 10.1021/jm801506m |
| format | Article |
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Med. Chem</addtitle><description>Highly potent N-substituted δ-lactams have been rationally designed and synthesized by a concise route with a one-pot tandem reaction as key step. These iminosugars show weak inhibition of wild-type β-glucocerebrosidase but 3- to 6-fold increases in mutant enzyme activity (N370S).</description><subject>Biological and medical sciences</subject><subject>Drug Design</subject><subject>Gaucher Disease - drug therapy</subject><subject>Gaucher Disease - genetics</subject><subject>Glucosylceramidase - antagonists & inhibitors</subject><subject>Glucosylceramidase - genetics</subject><subject>Humans</subject><subject>Imino Sugars - chemical synthesis</subject><subject>Imino Sugars - pharmacology</subject><subject>Lactams - chemical synthesis</subject><subject>Lactams - pharmacology</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Mutation, Missense</subject><subject>Pharmacology. 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Drug treatments</topic><topic>Structure-Activity Relationship</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Guan-Nan</creatorcontrib><creatorcontrib>Reinkensmeier, Gabriele</creatorcontrib><creatorcontrib>Zhang, Si-Wei</creatorcontrib><creatorcontrib>Zhou, Jian</creatorcontrib><creatorcontrib>Zhang, Liang-Ren</creatorcontrib><creatorcontrib>Zhang, Li-He</creatorcontrib><creatorcontrib>Butters, Terry D</creatorcontrib><creatorcontrib>Ye, Xin-Shan</creatorcontrib><collection>Pascal-Francis</collection><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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Guan-Nan</au><au>Reinkensmeier, Gabriele</au><au>Zhang, Si-Wei</au><au>Zhou, Jian</au><au>Zhang, Liang-Ren</au><au>Zhang, Li-He</au><au>Butters, Terry D</au><au>Ye, Xin-Shan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rational Design and Synthesis of Highly Potent Pharmacological Chaperones for Treatment of N370S Mutant Gaucher Disease</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2009-05-28</date><risdate>2009</risdate><volume>52</volume><issue>10</issue><spage>3146</spage><epage>3149</epage><pages>3146-3149</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Highly potent N-substituted δ-lactams have been rationally designed and synthesized by a concise route with a one-pot tandem reaction as key step. These iminosugars show weak inhibition of wild-type β-glucocerebrosidase but 3- to 6-fold increases in mutant enzyme activity (N370S).</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19397268</pmid><doi>10.1021/jm801506m</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2009-05, Vol.52 (10), p.3146-3149 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Biological and medical sciences Drug Design Gaucher Disease - drug therapy Gaucher Disease - genetics Glucosylceramidase - antagonists & inhibitors Glucosylceramidase - genetics Humans Imino Sugars - chemical synthesis Imino Sugars - pharmacology Lactams - chemical synthesis Lactams - pharmacology Medical sciences Miscellaneous Mutation, Missense Pharmacology. Drug treatments Structure-Activity Relationship Substrate Specificity |
| title | Rational Design and Synthesis of Highly Potent Pharmacological Chaperones for Treatment of N370S Mutant Gaucher Disease |
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