New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties
Insulin resistance in the liver and peripheral tissues together with a pancreatic cell defect are the common causes of type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor....
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| Veröffentlicht in: | Journal of medicinal chemistry 2000-03, Vol.43 (5), p.995-1010 |
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| container_title | Journal of medicinal chemistry |
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| creator | Malamas, Michael S Sredy, Janet Gunawan, Iwan Mihan, Brenda Sawicki, Diane R Seestaller, Laura Sullivan, Donald Flam, Brenda R |
| description | Insulin resistance in the liver and peripheral tissues together with a pancreatic cell defect are the common causes of type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibiton of PTPases may be an effective method in the treatment of type 2 diabetes. A series of azolidinediones has been prepared as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Several compounds were potent inhibitors against the recombinant rat and human PTP1B enzymes with submicromolar IC50 values. Elongated spacers between the azolidinedione moiety and the central aromatic portion of the molecule as well as hydrophobic groups at the vicinity of this aromatic region were very important to the inhibitory activity. Oxadiazolidinediones 87 and 88 and the corresponding acetic acid analogues 119 and 120 were the best h-PTP1B inhibitors with IC50 values in the range of 0.12−0.3 μM. Several compounds normalized plasma glucose and insulin levels in the ob/ob and db/db diabetic mouse models. |
| doi_str_mv | 10.1021/jm990476x |
| format | Article |
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It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibiton of PTPases may be an effective method in the treatment of type 2 diabetes. A series of azolidinediones has been prepared as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Several compounds were potent inhibitors against the recombinant rat and human PTP1B enzymes with submicromolar IC50 values. Elongated spacers between the azolidinedione moiety and the central aromatic portion of the molecule as well as hydrophobic groups at the vicinity of this aromatic region were very important to the inhibitory activity. Oxadiazolidinediones 87 and 88 and the corresponding acetic acid analogues 119 and 120 were the best h-PTP1B inhibitors with IC50 values in the range of 0.12−0.3 μM. Several compounds normalized plasma glucose and insulin levels in the ob/ob and db/db diabetic mouse models.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm990476x</identifier><identifier>PMID: 10715163</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>4-Nitrophenylphosphatase - antagonists & inhibitors ; Animals ; Biological and medical sciences ; Blood Glucose - metabolism ; Diabetes Mellitus, Type 2 - blood ; Diabetes Mellitus, Type 2 - genetics ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; General and cellular metabolism. Vitamins ; Humans ; Hypoglycemic Agents - chemical synthesis ; Hypoglycemic Agents - chemistry ; Hypoglycemic Agents - pharmacology ; In Vitro Techniques ; Insulin - blood ; Liver - drug effects ; Liver - enzymology ; Male ; Medical sciences ; Membrane Proteins - antagonists & inhibitors ; Mice ; Mice, Obese ; Oxazoles - chemical synthesis ; Oxazoles - chemistry ; Oxazoles - pharmacology ; Pharmacology. Drug treatments ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; Protein Tyrosine Phosphatases - antagonists & inhibitors ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins - antagonists & inhibitors ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2000-03, Vol.43 (5), p.995-1010</ispartof><rights>Copyright © 2000 American Chemical Society</rights><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a310t-c945d1113fe88819158824cc74ae1ff6b1f747c8fd0448688c5ca30a7f5914133</citedby><cites>FETCH-LOGICAL-a310t-c945d1113fe88819158824cc74ae1ff6b1f747c8fd0448688c5ca30a7f5914133</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm990476x$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm990476x$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1316456$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10715163$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Malamas, Michael S</creatorcontrib><creatorcontrib>Sredy, Janet</creatorcontrib><creatorcontrib>Gunawan, Iwan</creatorcontrib><creatorcontrib>Mihan, Brenda</creatorcontrib><creatorcontrib>Sawicki, Diane R</creatorcontrib><creatorcontrib>Seestaller, Laura</creatorcontrib><creatorcontrib>Sullivan, Donald</creatorcontrib><creatorcontrib>Flam, Brenda R</creatorcontrib><title>New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Insulin resistance in the liver and peripheral tissues together with a pancreatic cell defect are the common causes of type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibiton of PTPases may be an effective method in the treatment of type 2 diabetes. A series of azolidinediones has been prepared as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Several compounds were potent inhibitors against the recombinant rat and human PTP1B enzymes with submicromolar IC50 values. Elongated spacers between the azolidinedione moiety and the central aromatic portion of the molecule as well as hydrophobic groups at the vicinity of this aromatic region were very important to the inhibitory activity. Oxadiazolidinediones 87 and 88 and the corresponding acetic acid analogues 119 and 120 were the best h-PTP1B inhibitors with IC50 values in the range of 0.12−0.3 μM. Several compounds normalized plasma glucose and insulin levels in the ob/ob and db/db diabetic mouse models.</description><subject>4-Nitrophenylphosphatase - antagonists & inhibitors</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - metabolism</subject><subject>Diabetes Mellitus, Type 2 - blood</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Humans</subject><subject>Hypoglycemic Agents - chemical synthesis</subject><subject>Hypoglycemic Agents - chemistry</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>In Vitro Techniques</subject><subject>Insulin - blood</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membrane Proteins - antagonists & inhibitors</subject><subject>Mice</subject><subject>Mice, Obese</subject><subject>Oxazoles - chemical synthesis</subject><subject>Oxazoles - chemistry</subject><subject>Oxazoles - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 1</subject><subject>Protein Tyrosine Phosphatases - antagonists & inhibitors</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0E1v1DAQBmALgehSOPAHkA-AxCHgiT9z3FZACxWsxCKOltexiZck3tpetcuvJ1VWhQMna-RnRjMvQs-BvAVSw7vt0DSESXH7AC2A16RiirCHaEFIXVe1qOkJepLzlhBCoaaP0QkQCRwEXSD_xd3g5e_YhzaMrg1xdBmbjC_HLmxCiSnj6PEqxeLCiNeHFPPk8KqLedeZYrLDcIZvQunwciyhO-xc-tkfrBuCvWubyhJcfooeedNn9-z4nqLvH96vzy-qq68fL8-XV5WhQEplG8ZbAKDeKaWgAa5UzayVzDjwXmzASyat8i1hTAmlLLeGEiM9b4ABpafo9Tx3l-L13uWih5Ct63szurjPWpJG1ED4BN_M0E4X5eS83qUwmHTQQPRdqPo-1Mm-OA7dbwbX_iPnFCfw8ghMtqb3yYw25L-OgmBcTKyaWcjF3d5_m_RLC0kl1-vVN33xWZ79YGKlP03-1eyNzXob92mcovvPfn8AWxeaMw</recordid><startdate>20000309</startdate><enddate>20000309</enddate><creator>Malamas, Michael S</creator><creator>Sredy, Janet</creator><creator>Gunawan, Iwan</creator><creator>Mihan, Brenda</creator><creator>Sawicki, Diane R</creator><creator>Seestaller, Laura</creator><creator>Sullivan, Donald</creator><creator>Flam, Brenda R</creator><general>American Chemical Society</general><scope>BSCLL</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></search><sort><creationdate>20000309</creationdate><title>New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties</title><author>Malamas, Michael S ; Sredy, Janet ; Gunawan, Iwan ; Mihan, Brenda ; Sawicki, Diane R ; Seestaller, Laura ; Sullivan, Donald ; Flam, Brenda R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a310t-c945d1113fe88819158824cc74ae1ff6b1f747c8fd0448688c5ca30a7f5914133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>4-Nitrophenylphosphatase - antagonists & inhibitors</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Glucose - metabolism</topic><topic>Diabetes Mellitus, Type 2 - blood</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Humans</topic><topic>Hypoglycemic Agents - chemical synthesis</topic><topic>Hypoglycemic Agents - chemistry</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>In Vitro Techniques</topic><topic>Insulin - blood</topic><topic>Liver - drug effects</topic><topic>Liver - enzymology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Membrane Proteins - antagonists & inhibitors</topic><topic>Mice</topic><topic>Mice, Obese</topic><topic>Oxazoles - chemical synthesis</topic><topic>Oxazoles - chemistry</topic><topic>Oxazoles - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Tyrosine Phosphatase, Non-Receptor Type 1</topic><topic>Protein Tyrosine Phosphatases - antagonists & inhibitors</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Malamas, Michael S</creatorcontrib><creatorcontrib>Sredy, Janet</creatorcontrib><creatorcontrib>Gunawan, Iwan</creatorcontrib><creatorcontrib>Mihan, Brenda</creatorcontrib><creatorcontrib>Sawicki, Diane R</creatorcontrib><creatorcontrib>Seestaller, Laura</creatorcontrib><creatorcontrib>Sullivan, Donald</creatorcontrib><creatorcontrib>Flam, Brenda R</creatorcontrib><collection>Istex</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Malamas, Michael S</au><au>Sredy, Janet</au><au>Gunawan, Iwan</au><au>Mihan, Brenda</au><au>Sawicki, Diane R</au><au>Seestaller, Laura</au><au>Sullivan, Donald</au><au>Flam, Brenda R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2000-03-09</date><risdate>2000</risdate><volume>43</volume><issue>5</issue><spage>995</spage><epage>1010</epage><pages>995-1010</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Insulin resistance in the liver and peripheral tissues together with a pancreatic cell defect are the common causes of type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibiton of PTPases may be an effective method in the treatment of type 2 diabetes. A series of azolidinediones has been prepared as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Several compounds were potent inhibitors against the recombinant rat and human PTP1B enzymes with submicromolar IC50 values. 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| ispartof | Journal of medicinal chemistry, 2000-03, Vol.43 (5), p.995-1010 |
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| subjects | 4-Nitrophenylphosphatase - antagonists & inhibitors Animals Biological and medical sciences Blood Glucose - metabolism Diabetes Mellitus, Type 2 - blood Diabetes Mellitus, Type 2 - genetics Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General and cellular metabolism. Vitamins Humans Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - chemistry Hypoglycemic Agents - pharmacology In Vitro Techniques Insulin - blood Liver - drug effects Liver - enzymology Male Medical sciences Membrane Proteins - antagonists & inhibitors Mice Mice, Obese Oxazoles - chemical synthesis Oxazoles - chemistry Oxazoles - pharmacology Pharmacology. Drug treatments Protein Tyrosine Phosphatase, Non-Receptor Type 1 Protein Tyrosine Phosphatases - antagonists & inhibitors Rats Rats, Sprague-Dawley Recombinant Proteins - antagonists & inhibitors Structure-Activity Relationship |
| title | New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties |
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