Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners
Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole at the distal ring position were identified as potential antidiabetic agents. A selected compound demonstrated reasonable urinary glucose excretion and glucosuria in normal SD rats along with favorable blood glucose-lowering effect...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2010-03, Vol.18 (6), p.2178-2194 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Lee, Junwon Lee, Sung-Han Seo, Hee Jeong Son, Eun-Jung Lee, Suk Ho Jung, Myung Eun Lee, MinWoo Han, Ho-Kyun Kim, Jeongmin Kang, Jahyo Lee, Jinhwa |
| description | Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole at the distal ring position were identified as potential antidiabetic agents. A selected compound demonstrated reasonable urinary glucose excretion and glucosuria in normal SD rats along with favorable blood glucose-lowering effects in db/db mice.
Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine
59, 2-furan
61, and 3-thiophene
71 showed the best in vitro inhibitory activities to date (IC
50
=
3.51–7.03
nM) against SGLT2. A selected compound
61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related. |
| doi_str_mv | 10.1016/j.bmc.2010.01.073 |
| format | Article |
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Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine
59, 2-furan
61, and 3-thiophene
71 showed the best in vitro inhibitory activities to date (IC
50
=
3.51–7.03
nM) against SGLT2. A selected compound
61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2010.01.073</identifier><identifier>PMID: 20181486</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Dapagliflozin ; Diabetes ; Diabetic Nephropathies - drug therapy ; Drug Design ; Glucoside ; Glucosides - chemical synthesis ; Glucosides - chemistry ; Glucosides - pharmacology ; Humans ; Hypoglycemic Agents - chemical synthesis ; Hypoglycemic Agents - chemistry ; Hypoglycemic Agents - pharmacology ; Male ; Mice ; Mice, Inbred Strains ; Molecular Structure ; Rats ; Rats, Sprague-Dawley ; SGLT ; Sodium-Glucose Transporter 2 - antagonists & inhibitors ; Sodium-Glucose Transporter 2 - metabolism ; Stereoisomerism ; Structure-Activity Relationship ; Thiadiazole ; Thiadiazoles - chemical synthesis ; Thiadiazoles - chemistry ; Thiadiazoles - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry, 2010-03, Vol.18 (6), p.2178-2194</ispartof><rights>2010 Elsevier Ltd</rights><rights>Copyright 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c352t-ae534d096ee09f5f42ce4564608d1f796d6daf6eb4ef1750ce5b4c8373edee823</citedby><cites>FETCH-LOGICAL-c352t-ae534d096ee09f5f42ce4564608d1f796d6daf6eb4ef1750ce5b4c8373edee823</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089610001045$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20181486$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Junwon</creatorcontrib><creatorcontrib>Lee, Sung-Han</creatorcontrib><creatorcontrib>Seo, Hee Jeong</creatorcontrib><creatorcontrib>Son, Eun-Jung</creatorcontrib><creatorcontrib>Lee, Suk Ho</creatorcontrib><creatorcontrib>Jung, Myung Eun</creatorcontrib><creatorcontrib>Lee, MinWoo</creatorcontrib><creatorcontrib>Han, Ho-Kyun</creatorcontrib><creatorcontrib>Kim, Jeongmin</creatorcontrib><creatorcontrib>Kang, Jahyo</creatorcontrib><creatorcontrib>Lee, Jinhwa</creatorcontrib><title>Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole at the distal ring position were identified as potential antidiabetic agents. A selected compound demonstrated reasonable urinary glucose excretion and glucosuria in normal SD rats along with favorable blood glucose-lowering effects in db/db mice.
Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine
59, 2-furan
61, and 3-thiophene
71 showed the best in vitro inhibitory activities to date (IC
50
=
3.51–7.03
nM) against SGLT2. A selected compound
61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related.</description><subject>Animals</subject><subject>Dapagliflozin</subject><subject>Diabetes</subject><subject>Diabetic Nephropathies - drug therapy</subject><subject>Drug Design</subject><subject>Glucoside</subject><subject>Glucosides - chemical synthesis</subject><subject>Glucosides - chemistry</subject><subject>Glucosides - pharmacology</subject><subject>Humans</subject><subject>Hypoglycemic Agents - chemical synthesis</subject><subject>Hypoglycemic Agents - chemistry</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred Strains</subject><subject>Molecular Structure</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>SGLT</subject><subject>Sodium-Glucose Transporter 2 - antagonists & inhibitors</subject><subject>Sodium-Glucose Transporter 2 - metabolism</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Thiadiazole</subject><subject>Thiadiazoles - chemical synthesis</subject><subject>Thiadiazoles - chemistry</subject><subject>Thiadiazoles - pharmacology</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtPwzAQhC0EgvL4AVyQb1xIsWPHSeCEKl5SBQfK2XLsDXXlxMVOkYr48RgVkLhwWu3uzEjzIXRMyZgSKs4X46bT45ykndAxKdkWGlEueMZYTbfRiNSiykhViz20H-OCEJLzmu6ivWSpKK_ECH08-DdweJKpsHb4xa20j9YAfrqdznJs-7lt7OBDxCripR-gH6xyWKVhrGpgsBqrl3SNF5iesTOezeZWpde7d2vXwTBfu-Uc-j_Z2vfJAiEeop1WuQhH3_MAPd9czyZ32fTx9n5yNc00K_IhU1AwblIZAFK3RctzDbwQXJDK0LashRFGtQIaDi0tC6KhaLiuWMnAAFQ5O0Cnm9xl8K8riIPsbNTgnOrBr6IsGRM5L4siKelGqYOPMUArl8F2iY2kRH4xlwuZmMsv5pJQmZgnz8l3-qrpwPw6fiAnweVGAKnjm4Ugo7bQazA2gB6k8faf-E_Wy5PC</recordid><startdate>20100315</startdate><enddate>20100315</enddate><creator>Lee, Junwon</creator><creator>Lee, Sung-Han</creator><creator>Seo, Hee Jeong</creator><creator>Son, Eun-Jung</creator><creator>Lee, Suk Ho</creator><creator>Jung, Myung Eun</creator><creator>Lee, MinWoo</creator><creator>Han, Ho-Kyun</creator><creator>Kim, Jeongmin</creator><creator>Kang, Jahyo</creator><creator>Lee, Jinhwa</creator><general>Elsevier Ltd</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>20100315</creationdate><title>Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners</title><author>Lee, Junwon ; Lee, Sung-Han ; Seo, Hee Jeong ; Son, Eun-Jung ; Lee, Suk Ho ; Jung, Myung Eun ; Lee, MinWoo ; Han, Ho-Kyun ; Kim, Jeongmin ; Kang, Jahyo ; Lee, Jinhwa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c352t-ae534d096ee09f5f42ce4564608d1f796d6daf6eb4ef1750ce5b4c8373edee823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Dapagliflozin</topic><topic>Diabetes</topic><topic>Diabetic Nephropathies - drug therapy</topic><topic>Drug Design</topic><topic>Glucoside</topic><topic>Glucosides - chemical synthesis</topic><topic>Glucosides - chemistry</topic><topic>Glucosides - pharmacology</topic><topic>Humans</topic><topic>Hypoglycemic Agents - chemical synthesis</topic><topic>Hypoglycemic Agents - chemistry</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred Strains</topic><topic>Molecular Structure</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>SGLT</topic><topic>Sodium-Glucose Transporter 2 - antagonists & inhibitors</topic><topic>Sodium-Glucose Transporter 2 - metabolism</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Thiadiazole</topic><topic>Thiadiazoles - chemical synthesis</topic><topic>Thiadiazoles - chemistry</topic><topic>Thiadiazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Junwon</creatorcontrib><creatorcontrib>Lee, Sung-Han</creatorcontrib><creatorcontrib>Seo, Hee Jeong</creatorcontrib><creatorcontrib>Son, Eun-Jung</creatorcontrib><creatorcontrib>Lee, Suk Ho</creatorcontrib><creatorcontrib>Jung, Myung Eun</creatorcontrib><creatorcontrib>Lee, MinWoo</creatorcontrib><creatorcontrib>Han, Ho-Kyun</creatorcontrib><creatorcontrib>Kim, Jeongmin</creatorcontrib><creatorcontrib>Kang, Jahyo</creatorcontrib><creatorcontrib>Lee, Jinhwa</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>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Junwon</au><au>Lee, Sung-Han</au><au>Seo, Hee Jeong</au><au>Son, Eun-Jung</au><au>Lee, Suk Ho</au><au>Jung, Myung Eun</au><au>Lee, MinWoo</au><au>Han, Ho-Kyun</au><au>Kim, Jeongmin</au><au>Kang, Jahyo</au><au>Lee, Jinhwa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2010-03-15</date><risdate>2010</risdate><volume>18</volume><issue>6</issue><spage>2178</spage><epage>2194</epage><pages>2178-2194</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole at the distal ring position were identified as potential antidiabetic agents. A selected compound demonstrated reasonable urinary glucose excretion and glucosuria in normal SD rats along with favorable blood glucose-lowering effects in db/db mice.
Novel C-aryl glucoside SGLT2 inhibitors containing 1,3,4-thiadiazole moieties were designed and synthesized. Among the compounds tested, biaryl-type compounds containing pyrazine
59, 2-furan
61, and 3-thiophene
71 showed the best in vitro inhibitory activities to date (IC
50
=
3.51–7.03
nM) against SGLT2. A selected compound
61, demonstrated reasonable blood glucose-lowering effects, indicating that the information obtained from the SAR studies in this 1,3,4-thiadiazolylmethylphenyl glucoside series might help to design more active SGLT2 inhibitors that are structurally related.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>20181486</pmid><doi>10.1016/j.bmc.2010.01.073</doi><tpages>17</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry, 2010-03, Vol.18 (6), p.2178-2194 |
| issn | 0968-0896 1464-3391 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Dapagliflozin Diabetes Diabetic Nephropathies - drug therapy Drug Design Glucoside Glucosides - chemical synthesis Glucosides - chemistry Glucosides - pharmacology Humans Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - chemistry Hypoglycemic Agents - pharmacology Male Mice Mice, Inbred Strains Molecular Structure Rats Rats, Sprague-Dawley SGLT Sodium-Glucose Transporter 2 - antagonists & inhibitors Sodium-Glucose Transporter 2 - metabolism Stereoisomerism Structure-Activity Relationship Thiadiazole Thiadiazoles - chemical synthesis Thiadiazoles - chemistry Thiadiazoles - pharmacology |
| title | Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners |
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