Dipeptide Boronic Acid Inhibitors of Dipeptidyl Peptidase IV: Determinants of Potency and in Vivo Efficacy and Safety
Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a conce...
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-10, Vol.51 (19), p.6005-6013 |
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| creator | Connolly, Beth A Sanford, David G Chiluwal, Amrita K Healey, Sarah E Peters, Diane E Dimare, Matthew T Wu, Wengen Liu, Yuxin Maw, Hlaing Zhou, Yuhong Li, Youhua Jin, Zhiping Sudmeier, James L Lai, Jack H Bachovchin, William W |
| description | Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (>500) in rodents. |
| doi_str_mv | 10.1021/jm800390n |
| format | Article |
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Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (>500) in rodents.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm800390n</identifier><identifier>PMID: 18783201</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject><![CDATA[Administration, Oral ; Animals ; Biological and medical sciences ; Blood Glucose - analysis ; Blood Glucose - metabolism ; Boronic Acids - administration & dosage ; Boronic Acids - chemistry ; Boronic Acids - pharmacology ; Cell Line ; Cloning, Molecular ; Dipeptides - administration & dosage ; Dipeptides - chemistry ; Dipeptides - pharmacology ; Dipeptidyl Peptidase 4 - blood ; Dipeptidyl Peptidase 4 - isolation & purification ; Dipeptidyl-Peptidase IV Inhibitors ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - biosynthesis ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Drug-Related Side Effects and Adverse Reactions ; Female ; General and cellular metabolism. Vitamins ; Glucose - administration & dosage ; Glucose Tolerance Test ; Humans ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Molecular Conformation ; Peptide Library ; Pharmacology. Drug treatments ; Rats ; Rats, Sprague-Dawley ; Serine Proteinase Inhibitors - administration & dosage ; Serine Proteinase Inhibitors - chemistry ; Serine Proteinase Inhibitors - pharmacology ; Structure-Activity Relationship ; Substrate Specificity ; Time Factors]]></subject><ispartof>Journal of medicinal chemistry, 2008-10, Vol.51 (19), p.6005-6013</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-575dfca0b07f7667df83d62823177eb2246a74d614e51d60136e561eca34886a3</citedby><cites>FETCH-LOGICAL-a381t-575dfca0b07f7667df83d62823177eb2246a74d614e51d60136e561eca34886a3</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/jm800390n$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm800390n$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20746749$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18783201$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Connolly, Beth A</creatorcontrib><creatorcontrib>Sanford, David G</creatorcontrib><creatorcontrib>Chiluwal, Amrita K</creatorcontrib><creatorcontrib>Healey, Sarah E</creatorcontrib><creatorcontrib>Peters, Diane E</creatorcontrib><creatorcontrib>Dimare, Matthew T</creatorcontrib><creatorcontrib>Wu, Wengen</creatorcontrib><creatorcontrib>Liu, Yuxin</creatorcontrib><creatorcontrib>Maw, Hlaing</creatorcontrib><creatorcontrib>Zhou, Yuhong</creatorcontrib><creatorcontrib>Li, Youhua</creatorcontrib><creatorcontrib>Jin, Zhiping</creatorcontrib><creatorcontrib>Sudmeier, James L</creatorcontrib><creatorcontrib>Lai, Jack H</creatorcontrib><creatorcontrib>Bachovchin, William W</creatorcontrib><title>Dipeptide Boronic Acid Inhibitors of Dipeptidyl Peptidase IV: Determinants of Potency and in Vivo Efficacy and Safety</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (>500) in rodents.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - analysis</subject><subject>Blood Glucose - metabolism</subject><subject>Boronic Acids - administration & dosage</subject><subject>Boronic Acids - chemistry</subject><subject>Boronic Acids - pharmacology</subject><subject>Cell Line</subject><subject>Cloning, Molecular</subject><subject>Dipeptides - administration & dosage</subject><subject>Dipeptides - chemistry</subject><subject>Dipeptides - pharmacology</subject><subject>Dipeptidyl Peptidase 4 - blood</subject><subject>Dipeptidyl Peptidase 4 - isolation & purification</subject><subject>Dipeptidyl-Peptidase IV Inhibitors</subject><subject>Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors</subject><subject>Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - biosynthesis</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drug-Related Side Effects and Adverse Reactions</subject><subject>Female</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Glucose - administration & dosage</subject><subject>Glucose Tolerance Test</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Conformation</subject><subject>Peptide Library</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Serine Proteinase Inhibitors - administration & dosage</subject><subject>Serine Proteinase Inhibitors - chemistry</subject><subject>Serine Proteinase Inhibitors - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Substrate Specificity</subject><subject>Time Factors</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0EtLAzEQB_AgitbHwS8guXjwsJrHbpJ6822hYPEJXsI0D0xtsyXZiv32rrbWi6cZZn4Mwx-hfUqOKWH0ZDRRhPAuiWuoQytGilKRch11CGGsYILxLbSd84i0iDK-ibaokoozQjtodhmmbtoE6_B5neoYDD4zweJefAvD0NQp49rjXzQf48FPA9nh3vMpvnSNS5MQITY_cFA3Lpo5hmhxiPg5fNT4yvtgYDl8AO-a-S7a8DDObm9Zd9DT9dXjxW3Rv7vpXZz1C-CKNkUlK-sNkCGRXgohrVfcCqYYp1K6IWOlAFlaQUtXUSsI5cJVgjoDvFRKAN9BR4u7JtU5J-f1NIUJpLmmRH9Hp1fRtfZgYaez4cTZP7nMqgWHSwDZwNgniCbklWNElkKW3dYVCxdy4z5Xe0jvWkguK_04eNCv9y9Vi_u6-3cXTNajepZiG8k_D34BHGGQvA</recordid><startdate>20081009</startdate><enddate>20081009</enddate><creator>Connolly, Beth A</creator><creator>Sanford, David G</creator><creator>Chiluwal, Amrita K</creator><creator>Healey, Sarah E</creator><creator>Peters, Diane E</creator><creator>Dimare, Matthew T</creator><creator>Wu, Wengen</creator><creator>Liu, Yuxin</creator><creator>Maw, Hlaing</creator><creator>Zhou, Yuhong</creator><creator>Li, Youhua</creator><creator>Jin, Zhiping</creator><creator>Sudmeier, James L</creator><creator>Lai, Jack H</creator><creator>Bachovchin, William W</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></search><sort><creationdate>20081009</creationdate><title>Dipeptide Boronic Acid Inhibitors of Dipeptidyl Peptidase IV: Determinants of Potency and in Vivo Efficacy and Safety</title><author>Connolly, Beth A ; Sanford, David G ; Chiluwal, Amrita K ; Healey, Sarah E ; Peters, Diane E ; Dimare, Matthew T ; Wu, Wengen ; Liu, Yuxin ; Maw, Hlaing ; Zhou, Yuhong ; Li, Youhua ; Jin, Zhiping ; Sudmeier, James L ; Lai, Jack H ; Bachovchin, William W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-575dfca0b07f7667df83d62823177eb2246a74d614e51d60136e561eca34886a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Glucose - analysis</topic><topic>Blood Glucose - metabolism</topic><topic>Boronic Acids - administration & dosage</topic><topic>Boronic Acids - chemistry</topic><topic>Boronic Acids - pharmacology</topic><topic>Cell Line</topic><topic>Cloning, Molecular</topic><topic>Dipeptides - administration & dosage</topic><topic>Dipeptides - chemistry</topic><topic>Dipeptides - pharmacology</topic><topic>Dipeptidyl Peptidase 4 - blood</topic><topic>Dipeptidyl Peptidase 4 - isolation & purification</topic><topic>Dipeptidyl-Peptidase IV Inhibitors</topic><topic>Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors</topic><topic>Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - biosynthesis</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drug-Related Side Effects and Adverse Reactions</topic><topic>Female</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Glucose - administration & dosage</topic><topic>Glucose Tolerance Test</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular Conformation</topic><topic>Peptide Library</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Serine Proteinase Inhibitors - administration & dosage</topic><topic>Serine Proteinase Inhibitors - chemistry</topic><topic>Serine Proteinase Inhibitors - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Substrate Specificity</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Connolly, Beth A</creatorcontrib><creatorcontrib>Sanford, David G</creatorcontrib><creatorcontrib>Chiluwal, Amrita K</creatorcontrib><creatorcontrib>Healey, Sarah E</creatorcontrib><creatorcontrib>Peters, Diane E</creatorcontrib><creatorcontrib>Dimare, Matthew T</creatorcontrib><creatorcontrib>Wu, Wengen</creatorcontrib><creatorcontrib>Liu, Yuxin</creatorcontrib><creatorcontrib>Maw, Hlaing</creatorcontrib><creatorcontrib>Zhou, Yuhong</creatorcontrib><creatorcontrib>Li, Youhua</creatorcontrib><creatorcontrib>Jin, Zhiping</creatorcontrib><creatorcontrib>Sudmeier, James L</creatorcontrib><creatorcontrib>Lai, Jack H</creatorcontrib><creatorcontrib>Bachovchin, William W</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Connolly, Beth A</au><au>Sanford, David G</au><au>Chiluwal, Amrita K</au><au>Healey, Sarah E</au><au>Peters, Diane E</au><au>Dimare, Matthew T</au><au>Wu, Wengen</au><au>Liu, Yuxin</au><au>Maw, Hlaing</au><au>Zhou, Yuhong</au><au>Li, Youhua</au><au>Jin, Zhiping</au><au>Sudmeier, James L</au><au>Lai, Jack H</au><au>Bachovchin, William W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dipeptide Boronic Acid Inhibitors of Dipeptidyl Peptidase IV: Determinants of Potency and in Vivo Efficacy and Safety</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-10-09</date><risdate>2008</risdate><volume>51</volume><issue>19</issue><spage>6005</spage><epage>6013</epage><pages>6005-6013</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (>500) in rodents.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>18783201</pmid><doi>10.1021/jm800390n</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 2008-10, Vol.51 (19), p.6005-6013 |
| issn | 0022-2623 1520-4804 |
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| source | ACS Publications; MEDLINE |
| subjects | Administration, Oral Animals Biological and medical sciences Blood Glucose - analysis Blood Glucose - metabolism Boronic Acids - administration & dosage Boronic Acids - chemistry Boronic Acids - pharmacology Cell Line Cloning, Molecular Dipeptides - administration & dosage Dipeptides - chemistry Dipeptides - pharmacology Dipeptidyl Peptidase 4 - blood Dipeptidyl Peptidase 4 - isolation & purification Dipeptidyl-Peptidase IV Inhibitors Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - biosynthesis Dose-Response Relationship, Drug Drug Evaluation, Preclinical Drug-Related Side Effects and Adverse Reactions Female General and cellular metabolism. Vitamins Glucose - administration & dosage Glucose Tolerance Test Humans Male Medical sciences Mice Mice, Inbred C57BL Molecular Conformation Peptide Library Pharmacology. Drug treatments Rats Rats, Sprague-Dawley Serine Proteinase Inhibitors - administration & dosage Serine Proteinase Inhibitors - chemistry Serine Proteinase Inhibitors - pharmacology Structure-Activity Relationship Substrate Specificity Time Factors |
| title | Dipeptide Boronic Acid Inhibitors of Dipeptidyl Peptidase IV: Determinants of Potency and in Vivo Efficacy and Safety |
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