Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. Part 2: Synthesis of novel triplet drugs with the epoxymethano structure (capped homotriplet)
Capped homotriplet KNT-123 with high selectivity for the μ receptor over the κ receptor induced profound antinociception; the effect was 11-fold more potent than that of morphine in the acetic acid writhing assay. An improved synthetic method for triplet drugs with the 1,3,5-trioxazatriquinane skele...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-10, Vol.21 (20), p.6198-6202 |
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| creator | Nagase, Hiroshi Koyano, Koji Wada, Naohisa Hirayama, Shigeto Watanabe, Akio Nemoto, Toru Nakajima, Mayumi Nakao, Kaoru Mochizuki, Hidenori Fujii, Hideaki |
| description | Capped homotriplet KNT-123 with high selectivity for the μ receptor over the κ receptor induced profound antinociception; the effect was 11-fold more potent than that of morphine in the acetic acid writhing assay.
An improved synthetic method for triplet drugs with the 1,3,5-trioxazatriquinane skeleton was developed that used
p-toluenesulfonylmethyl isocyanide (TosMIC) instead of 1,3-dithiane. Using the improved method, we synthesized compounds with two identical pharmacophore units and an epoxymethano group, that is, capped homotriplets. Among the synthesized capped homotriplets, KNT-123 showed high selectivity for the μ receptor over the κ receptor, and the μ selectivity was the highest among the reported μ selective nonpeptide ligands. KNT-123 administered subcutaneously induced a dose-dependent analgesic effect in the acetic acid writhing assay, and its potency was 11-fold more potent than that of morphine. KNT-123 may serve as a useful tool for the study of the pharmacological actions mediated specifically via the μ receptor. |
| doi_str_mv | 10.1016/j.bmcl.2011.07.065 |
| format | Article |
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An improved synthetic method for triplet drugs with the 1,3,5-trioxazatriquinane skeleton was developed that used
p-toluenesulfonylmethyl isocyanide (TosMIC) instead of 1,3-dithiane. Using the improved method, we synthesized compounds with two identical pharmacophore units and an epoxymethano group, that is, capped homotriplets. Among the synthesized capped homotriplets, KNT-123 showed high selectivity for the μ receptor over the κ receptor, and the μ selectivity was the highest among the reported μ selective nonpeptide ligands. KNT-123 administered subcutaneously induced a dose-dependent analgesic effect in the acetic acid writhing assay, and its potency was 11-fold more potent than that of morphine. KNT-123 may serve as a useful tool for the study of the pharmacological actions mediated specifically via the μ receptor.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.07.065</identifier><identifier>PMID: 21889335</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>acetic acid ; analgesic effect ; Analgesics ; Analgesics, Opioid - chemical synthesis ; Analgesics, Opioid - chemistry ; Analgesics, Opioid - pharmacology ; Analgesics, Opioid - therapeutic use ; Animals ; Antinociception ; Biological and medical sciences ; Bridged-Ring Compounds - chemical synthesis ; Bridged-Ring Compounds - chemistry ; Bridged-Ring Compounds - pharmacology ; Bridged-Ring Compounds - therapeutic use ; Cap structure ; Capped homotriplet ; Medical sciences ; Mice ; Models, Molecular ; morphine ; Neuropharmacology ; Nitriles - chemical synthesis ; Nitriles - chemistry ; Nitriles - pharmacology ; Nitriles - therapeutic use ; Nociception - drug effects ; Nociceptive Pain - drug therapy ; Opioid ; p-Toluenesulfonylmethyl isocyanide ; Pain Measurement - drug effects ; Pharmacology. Drug treatments ; Receptors, Opioid, kappa - metabolism ; Receptors, Opioid, mu - metabolism ; Sesquiterpenes - chemical synthesis ; Sesquiterpenes - chemistry ; Sesquiterpenes - pharmacology ; Sesquiterpenes - therapeutic use ; Tosyl Compounds - chemical synthesis ; Tosyl Compounds - chemistry ; Tosyl Compounds - pharmacology ; Tosyl Compounds - therapeutic use</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-10, Vol.21 (20), p.6198-6202</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-9c3577dfd89663b084f8a2cdeaabab2225b555d28bbdbf0b51de10e8887c18b73</citedby><cites>FETCH-LOGICAL-c441t-9c3577dfd89663b084f8a2cdeaabab2225b555d28bbdbf0b51de10e8887c18b73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2011.07.065$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24600368$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21889335$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nagase, Hiroshi</creatorcontrib><creatorcontrib>Koyano, Koji</creatorcontrib><creatorcontrib>Wada, Naohisa</creatorcontrib><creatorcontrib>Hirayama, Shigeto</creatorcontrib><creatorcontrib>Watanabe, Akio</creatorcontrib><creatorcontrib>Nemoto, Toru</creatorcontrib><creatorcontrib>Nakajima, Mayumi</creatorcontrib><creatorcontrib>Nakao, Kaoru</creatorcontrib><creatorcontrib>Mochizuki, Hidenori</creatorcontrib><creatorcontrib>Fujii, Hideaki</creatorcontrib><title>Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. Part 2: Synthesis of novel triplet drugs with the epoxymethano structure (capped homotriplet)</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Capped homotriplet KNT-123 with high selectivity for the μ receptor over the κ receptor induced profound antinociception; the effect was 11-fold more potent than that of morphine in the acetic acid writhing assay.
An improved synthetic method for triplet drugs with the 1,3,5-trioxazatriquinane skeleton was developed that used
p-toluenesulfonylmethyl isocyanide (TosMIC) instead of 1,3-dithiane. Using the improved method, we synthesized compounds with two identical pharmacophore units and an epoxymethano group, that is, capped homotriplets. Among the synthesized capped homotriplets, KNT-123 showed high selectivity for the μ receptor over the κ receptor, and the μ selectivity was the highest among the reported μ selective nonpeptide ligands. KNT-123 administered subcutaneously induced a dose-dependent analgesic effect in the acetic acid writhing assay, and its potency was 11-fold more potent than that of morphine. KNT-123 may serve as a useful tool for the study of the pharmacological actions mediated specifically via the μ receptor.</description><subject>acetic acid</subject><subject>analgesic effect</subject><subject>Analgesics</subject><subject>Analgesics, Opioid - chemical synthesis</subject><subject>Analgesics, Opioid - chemistry</subject><subject>Analgesics, Opioid - pharmacology</subject><subject>Analgesics, Opioid - therapeutic use</subject><subject>Animals</subject><subject>Antinociception</subject><subject>Biological and medical sciences</subject><subject>Bridged-Ring Compounds - chemical synthesis</subject><subject>Bridged-Ring Compounds - chemistry</subject><subject>Bridged-Ring Compounds - pharmacology</subject><subject>Bridged-Ring Compounds - therapeutic use</subject><subject>Cap structure</subject><subject>Capped homotriplet</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>morphine</subject><subject>Neuropharmacology</subject><subject>Nitriles - chemical synthesis</subject><subject>Nitriles - chemistry</subject><subject>Nitriles - pharmacology</subject><subject>Nitriles - therapeutic use</subject><subject>Nociception - drug effects</subject><subject>Nociceptive Pain - drug therapy</subject><subject>Opioid</subject><subject>p-Toluenesulfonylmethyl isocyanide</subject><subject>Pain Measurement - drug effects</subject><subject>Pharmacology. Drug treatments</subject><subject>Receptors, Opioid, kappa - metabolism</subject><subject>Receptors, Opioid, mu - metabolism</subject><subject>Sesquiterpenes - chemical synthesis</subject><subject>Sesquiterpenes - chemistry</subject><subject>Sesquiterpenes - pharmacology</subject><subject>Sesquiterpenes - therapeutic use</subject><subject>Tosyl Compounds - chemical synthesis</subject><subject>Tosyl Compounds - chemistry</subject><subject>Tosyl Compounds - pharmacology</subject><subject>Tosyl Compounds - therapeutic use</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkk1v1DAQhiMEoqXwBziALwiQmmA7duIgLqjiS6oEUqnEzfLHZNdLEqe2U7r8On4aXu0CN9TTHOZ53xnNO0XxmOCKYNK82lR6NENFMSEVbivc8DvFMWENK2uG-d3iGHcNLkXHvh0VD2LcYEwYZux-cUSJEF1d8-Pi18V2SmuILiLfo8lfw4BScPMACdmwrCL64dIakdP6lJe54W_UT5Xr1eImNQGK3yGjfopITRZlJxfQvFZhVMYPfuUgVuiLCgnR1-h2ozKCYPY32xHSWk0exRQWk5YA6IVR8wwWrf3oD8qXD4t7vRoiPDrUk-Ly_buvZx_L888fPp29PS8NYySVnal529reiq5pao0F64WixoJSWmlKKdecc0uF1lb3WHNigWAQQrSGCN3WJ8Xzve8c_NUCMcnRRQPDkK_glyhF1xHW0Y7cgqxp27Rk50n3pAk-xgC9nIMbVdhKguUuYrmRu4jlLmKJW5kjzqInB_tFj2D_Sv5kmoFnB0BFo4Y-qMm4-I9jDcZ1IzL3dM_1yku1Cpm5vMiTeP6TmjPaZOLNnoB82GsHQUbjYDJgXQCTpPXuf5v-BpUa0wI</recordid><startdate>20111015</startdate><enddate>20111015</enddate><creator>Nagase, Hiroshi</creator><creator>Koyano, Koji</creator><creator>Wada, Naohisa</creator><creator>Hirayama, Shigeto</creator><creator>Watanabe, Akio</creator><creator>Nemoto, Toru</creator><creator>Nakajima, Mayumi</creator><creator>Nakao, Kaoru</creator><creator>Mochizuki, Hidenori</creator><creator>Fujii, Hideaki</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20111015</creationdate><title>Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. Part 2: Synthesis of novel triplet drugs with the epoxymethano structure (capped homotriplet)</title><author>Nagase, Hiroshi ; Koyano, Koji ; Wada, Naohisa ; Hirayama, Shigeto ; Watanabe, Akio ; Nemoto, Toru ; Nakajima, Mayumi ; Nakao, Kaoru ; Mochizuki, Hidenori ; Fujii, Hideaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-9c3577dfd89663b084f8a2cdeaabab2225b555d28bbdbf0b51de10e8887c18b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>acetic acid</topic><topic>analgesic effect</topic><topic>Analgesics</topic><topic>Analgesics, Opioid - chemical synthesis</topic><topic>Analgesics, Opioid - chemistry</topic><topic>Analgesics, Opioid - pharmacology</topic><topic>Analgesics, Opioid - therapeutic use</topic><topic>Animals</topic><topic>Antinociception</topic><topic>Biological and medical sciences</topic><topic>Bridged-Ring Compounds - chemical synthesis</topic><topic>Bridged-Ring Compounds - chemistry</topic><topic>Bridged-Ring Compounds - pharmacology</topic><topic>Bridged-Ring Compounds - therapeutic use</topic><topic>Cap structure</topic><topic>Capped homotriplet</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>morphine</topic><topic>Neuropharmacology</topic><topic>Nitriles - chemical synthesis</topic><topic>Nitriles - chemistry</topic><topic>Nitriles - pharmacology</topic><topic>Nitriles - therapeutic use</topic><topic>Nociception - drug effects</topic><topic>Nociceptive Pain - drug therapy</topic><topic>Opioid</topic><topic>p-Toluenesulfonylmethyl isocyanide</topic><topic>Pain Measurement - drug effects</topic><topic>Pharmacology. Drug treatments</topic><topic>Receptors, Opioid, kappa - metabolism</topic><topic>Receptors, Opioid, mu - metabolism</topic><topic>Sesquiterpenes - chemical synthesis</topic><topic>Sesquiterpenes - chemistry</topic><topic>Sesquiterpenes - pharmacology</topic><topic>Sesquiterpenes - therapeutic use</topic><topic>Tosyl Compounds - chemical synthesis</topic><topic>Tosyl Compounds - chemistry</topic><topic>Tosyl Compounds - pharmacology</topic><topic>Tosyl Compounds - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nagase, Hiroshi</creatorcontrib><creatorcontrib>Koyano, Koji</creatorcontrib><creatorcontrib>Wada, Naohisa</creatorcontrib><creatorcontrib>Hirayama, Shigeto</creatorcontrib><creatorcontrib>Watanabe, Akio</creatorcontrib><creatorcontrib>Nemoto, Toru</creatorcontrib><creatorcontrib>Nakajima, Mayumi</creatorcontrib><creatorcontrib>Nakao, Kaoru</creatorcontrib><creatorcontrib>Mochizuki, Hidenori</creatorcontrib><creatorcontrib>Fujii, Hideaki</creatorcontrib><collection>AGRIS</collection><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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nagase, Hiroshi</au><au>Koyano, Koji</au><au>Wada, Naohisa</au><au>Hirayama, Shigeto</au><au>Watanabe, Akio</au><au>Nemoto, Toru</au><au>Nakajima, Mayumi</au><au>Nakao, Kaoru</au><au>Mochizuki, Hidenori</au><au>Fujii, Hideaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. Part 2: Synthesis of novel triplet drugs with the epoxymethano structure (capped homotriplet)</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-10-15</date><risdate>2011</risdate><volume>21</volume><issue>20</issue><spage>6198</spage><epage>6202</epage><pages>6198-6202</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Capped homotriplet KNT-123 with high selectivity for the μ receptor over the κ receptor induced profound antinociception; the effect was 11-fold more potent than that of morphine in the acetic acid writhing assay.
An improved synthetic method for triplet drugs with the 1,3,5-trioxazatriquinane skeleton was developed that used
p-toluenesulfonylmethyl isocyanide (TosMIC) instead of 1,3-dithiane. Using the improved method, we synthesized compounds with two identical pharmacophore units and an epoxymethano group, that is, capped homotriplets. Among the synthesized capped homotriplets, KNT-123 showed high selectivity for the μ receptor over the κ receptor, and the μ selectivity was the highest among the reported μ selective nonpeptide ligands. KNT-123 administered subcutaneously induced a dose-dependent analgesic effect in the acetic acid writhing assay, and its potency was 11-fold more potent than that of morphine. KNT-123 may serve as a useful tool for the study of the pharmacological actions mediated specifically via the μ receptor.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21889335</pmid><doi>10.1016/j.bmcl.2011.07.065</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Bioorganic & medicinal chemistry letters, 2011-10, Vol.21 (20), p.6198-6202 |
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| subjects | acetic acid analgesic effect Analgesics Analgesics, Opioid - chemical synthesis Analgesics, Opioid - chemistry Analgesics, Opioid - pharmacology Analgesics, Opioid - therapeutic use Animals Antinociception Biological and medical sciences Bridged-Ring Compounds - chemical synthesis Bridged-Ring Compounds - chemistry Bridged-Ring Compounds - pharmacology Bridged-Ring Compounds - therapeutic use Cap structure Capped homotriplet Medical sciences Mice Models, Molecular morphine Neuropharmacology Nitriles - chemical synthesis Nitriles - chemistry Nitriles - pharmacology Nitriles - therapeutic use Nociception - drug effects Nociceptive Pain - drug therapy Opioid p-Toluenesulfonylmethyl isocyanide Pain Measurement - drug effects Pharmacology. Drug treatments Receptors, Opioid, kappa - metabolism Receptors, Opioid, mu - metabolism Sesquiterpenes - chemical synthesis Sesquiterpenes - chemistry Sesquiterpenes - pharmacology Sesquiterpenes - therapeutic use Tosyl Compounds - chemical synthesis Tosyl Compounds - chemistry Tosyl Compounds - pharmacology Tosyl Compounds - therapeutic use |
| title | Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. Part 2: Synthesis of novel triplet drugs with the epoxymethano structure (capped homotriplet) |
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