Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics
The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3β inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3β inhibitory activity in both cell-free a...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2012-02, Vol.20 (3), p.1188-1200 |
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| creator | Seto, Shigeki Yumoto, Kazuhiko Okada, Kyoko Asahina, Yoshikazu Iwane, Aya Iwago, Maki Terasawa, Reiko Shreder, Kevin R. Murakami, Koji Kohno, Yasushi |
| description | The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3β inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3β inhibitory activity in both cell-free and cell-based assays (IC50 = 36nM, EC50 = 3.2μM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice. |
| doi_str_mv | 10.1016/j.bmc.2011.12.046 |
| format | Article |
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Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3β inhibitory activity in both cell-free and cell-based assays (IC50 = 36nM, EC50 = 3.2μM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2011.12.046</identifier><identifier>PMID: 22261023</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Animals ; Biological and medical sciences ; blood glucose ; chemistry ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - enzymology ; Drug Design ; Glucose Tolerance Test ; glucose tolerance tests ; Glycogen Synthase Kinase 3 - antagonists & inhibitors ; Glycogen Synthase Kinase 3 - metabolism ; Glycogen Synthase Kinase 3 beta ; glycogen synthase kinases ; GSK-3β inhibitor ; Hep G2 Cells ; Humans ; inhibitory concentration 50 ; Male ; Medical sciences ; Mice ; Models, Molecular ; noninsulin-dependent diabetes mellitus ; Pharmacology. Drug treatments ; quinolones ; Quinolones - chemical synthesis ; Quinolones - chemistry ; Quinolones - pharmacokinetics ; Quinolones - pharmacology ; Spiro Compounds - chemical synthesis ; Spiro Compounds - chemistry ; Spiro Compounds - pharmacokinetics ; Spiro Compounds - pharmacology ; Spirocycle ; Tricyclic quinolones</subject><ispartof>Bioorganic & medicinal chemistry, 2012-02, Vol.20 (3), p.1188-1200</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. 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Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3β inhibitory activity in both cell-free and cell-based assays (IC50 = 36nM, EC50 = 3.2μM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>blood glucose</subject><subject>chemistry</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Diabetes Mellitus, Type 2 - enzymology</subject><subject>Drug Design</subject><subject>Glucose Tolerance Test</subject><subject>glucose tolerance tests</subject><subject>Glycogen Synthase Kinase 3 - antagonists & inhibitors</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>glycogen synthase kinases</subject><subject>GSK-3β inhibitor</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>inhibitory concentration 50</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>noninsulin-dependent diabetes mellitus</subject><subject>Pharmacology. Drug treatments</subject><subject>quinolones</subject><subject>Quinolones - chemical synthesis</subject><subject>Quinolones - chemistry</subject><subject>Quinolones - pharmacokinetics</subject><subject>Quinolones - pharmacology</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - chemistry</subject><subject>Spiro Compounds - pharmacokinetics</subject><subject>Spiro Compounds - pharmacology</subject><subject>Spirocycle</subject><subject>Tricyclic quinolones</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2O1DAQhS0EYpqBA7ABbxCwSPBfnESs0AgGxEgIDbO2HLvS4yZtN7a7pdyB03AQzoSjbmAHq6rF994r1UPoMSU1JVS-2tTD1tSMUFpTVhMh76AVFVJUnPf0LlqRXnYV6Xp5hh6ktCGEMNHT--iMMSYpYXyFvn_eOx-m4AFbiO6gsztAwib4rJ13fo1TjmUDi9POxWBmMwHWCYeop2nG2iwCvJ5mE9bgcZp9vtUJ8Ffnl8F__sAvLq8_VmV5iZ2_dYPLISY8hojzvAPMsHV6gOxMeojujXpK8Og0z9HNu7dfLt5XV58uP1y8uaqM4F2uGsY4lSOVWoxD23A79LThXMuRtcwaaWinLVAyWKtJ1xprG6a7duxFP7RWEH6Onh99dzF820PKauuSgWnSHsI-qb749x0T7P8k7Zq25aQpJD2SJoaUIoxqF91Wx1lRopa21EaVttTSlqJMlbaK5snJfT9swf5R_K6nAM9OgE5GT2PU3rj0l2tE24pmCX965EYdlF7Hwtxcl6SGlDRSflCI10cCyl8PDqJKxoE3YF0Ek5UN7h-H_gIThL32</recordid><startdate>20120201</startdate><enddate>20120201</enddate><creator>Seto, Shigeki</creator><creator>Yumoto, Kazuhiko</creator><creator>Okada, Kyoko</creator><creator>Asahina, Yoshikazu</creator><creator>Iwane, Aya</creator><creator>Iwago, Maki</creator><creator>Terasawa, Reiko</creator><creator>Shreder, Kevin R.</creator><creator>Murakami, Koji</creator><creator>Kohno, Yasushi</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>20120201</creationdate><title>Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics</title><author>Seto, Shigeki ; Yumoto, Kazuhiko ; Okada, Kyoko ; Asahina, Yoshikazu ; Iwane, Aya ; Iwago, Maki ; Terasawa, Reiko ; Shreder, Kevin R. ; Murakami, Koji ; Kohno, Yasushi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-522316f16a4fb753db91533a6f272dc6c18ade10bdda087cdd52a87f949b7d403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>blood glucose</topic><topic>chemistry</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Diabetes Mellitus, Type 2 - enzymology</topic><topic>Drug Design</topic><topic>Glucose Tolerance Test</topic><topic>glucose tolerance tests</topic><topic>Glycogen Synthase Kinase 3 - antagonists & inhibitors</topic><topic>Glycogen Synthase Kinase 3 - metabolism</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>glycogen synthase kinases</topic><topic>GSK-3β inhibitor</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>inhibitory concentration 50</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>noninsulin-dependent diabetes mellitus</topic><topic>Pharmacology. Drug treatments</topic><topic>quinolones</topic><topic>Quinolones - chemical synthesis</topic><topic>Quinolones - chemistry</topic><topic>Quinolones - pharmacokinetics</topic><topic>Quinolones - pharmacology</topic><topic>Spiro Compounds - chemical synthesis</topic><topic>Spiro Compounds - chemistry</topic><topic>Spiro Compounds - pharmacokinetics</topic><topic>Spiro Compounds - pharmacology</topic><topic>Spirocycle</topic><topic>Tricyclic quinolones</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Seto, Shigeki</creatorcontrib><creatorcontrib>Yumoto, Kazuhiko</creatorcontrib><creatorcontrib>Okada, Kyoko</creatorcontrib><creatorcontrib>Asahina, Yoshikazu</creatorcontrib><creatorcontrib>Iwane, Aya</creatorcontrib><creatorcontrib>Iwago, Maki</creatorcontrib><creatorcontrib>Terasawa, Reiko</creatorcontrib><creatorcontrib>Shreder, Kevin R.</creatorcontrib><creatorcontrib>Murakami, Koji</creatorcontrib><creatorcontrib>Kohno, Yasushi</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</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Seto, Shigeki</au><au>Yumoto, Kazuhiko</au><au>Okada, Kyoko</au><au>Asahina, Yoshikazu</au><au>Iwane, Aya</au><au>Iwago, Maki</au><au>Terasawa, Reiko</au><au>Shreder, Kevin R.</au><au>Murakami, Koji</au><au>Kohno, Yasushi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2012-02-01</date><risdate>2012</risdate><volume>20</volume><issue>3</issue><spage>1188</spage><epage>1200</epage><pages>1188-1200</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>The design, synthesis, and evaluation of 6-6-7 tricyclic quinolones containing the strained spirocycle moiety aiming at the GSK-3β inhibitor were described. Among the synthesized compounds, 44, having a cyclobutane ring on a spirocycle, showed excellent GSK-3β inhibitory activity in both cell-free and cell-based assays (IC50 = 36nM, EC50 = 3.2μM, respectively). Additionally, 44 decreased the plasma glucose concentration dose-dependently after an oral glucose tolerance test in mice.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22261023</pmid><doi>10.1016/j.bmc.2011.12.046</doi><tpages>13</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry, 2012-02, Vol.20 (3), p.1188-1200 |
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| language | eng |
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| subjects | Animals Biological and medical sciences blood glucose chemistry Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - enzymology Drug Design Glucose Tolerance Test glucose tolerance tests Glycogen Synthase Kinase 3 - antagonists & inhibitors Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta glycogen synthase kinases GSK-3β inhibitor Hep G2 Cells Humans inhibitory concentration 50 Male Medical sciences Mice Models, Molecular noninsulin-dependent diabetes mellitus Pharmacology. Drug treatments quinolones Quinolones - chemical synthesis Quinolones - chemistry Quinolones - pharmacokinetics Quinolones - pharmacology Spiro Compounds - chemical synthesis Spiro Compounds - chemistry Spiro Compounds - pharmacokinetics Spiro Compounds - pharmacology Spirocycle Tricyclic quinolones |
| title | Quinolone derivatives containing strained spirocycle as orally active glycogen synthase kinase 3β (GSK-3β) inhibitors for type 2 diabetics |
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