Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representat...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2006-02, Vol.16 (4), p.978-983 |
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| creator | Adkison, Kim K. Barrett, David G. Deaton, David N. Gampe, Robert T. Hassell, Anne M. Long, Stacey T. McFadyen, Robert B. Miller, Aaron B. Miller, Larry R. Payne, J. Alan Shewchuk, Lisa M. Wells-Knecht, Kevin J. Willard, Derril H. Wright, Lois L. |
| description | Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and
13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and
13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes. |
| doi_str_mv | 10.1016/j.bmcl.2005.10.108 |
| format | Article |
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13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and
13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2005.10.108</identifier><identifier>PMID: 16290936</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Aldehydes ; Aldehydes - chemistry ; Animals ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Cathepsin K ; Cathepsin K inhibitors ; Cathepsins - antagonists & inhibitors ; Crystallography, X-Ray ; Cysteine protease inhibitors ; Drug Evaluation, Preclinical ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Humans ; Hydrogen-Ion Concentration ; Hydrolysis ; Medical sciences ; Models, Molecular ; Molecular Conformation ; Pharmacology. Drug treatments ; Prodrugs ; Prodrugs - chemical synthesis ; Prodrugs - chemistry ; Prodrugs - pharmacology ; Rats ; Semicarbazones ; Semicarbazones - chemical synthesis ; Semicarbazones - chemistry ; Semicarbazones - pharmacology ; Solubility ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2006-02, Vol.16 (4), p.978-983</ispartof><rights>2005 Elsevier Ltd</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-1678f41a0b7ac1f15875d3c4b1a9c0d6aeca00cbbda9846855461088b989d6223</citedby><cites>FETCH-LOGICAL-c415t-1678f41a0b7ac1f15875d3c4b1a9c0d6aeca00cbbda9846855461088b989d6223</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X05013910$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17557085$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16290936$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Adkison, Kim K.</creatorcontrib><creatorcontrib>Barrett, David G.</creatorcontrib><creatorcontrib>Deaton, David N.</creatorcontrib><creatorcontrib>Gampe, Robert T.</creatorcontrib><creatorcontrib>Hassell, Anne M.</creatorcontrib><creatorcontrib>Long, Stacey T.</creatorcontrib><creatorcontrib>McFadyen, Robert B.</creatorcontrib><creatorcontrib>Miller, Aaron B.</creatorcontrib><creatorcontrib>Miller, Larry R.</creatorcontrib><creatorcontrib>Payne, J. Alan</creatorcontrib><creatorcontrib>Shewchuk, Lisa M.</creatorcontrib><creatorcontrib>Wells-Knecht, Kevin J.</creatorcontrib><creatorcontrib>Willard, Derril H.</creatorcontrib><creatorcontrib>Wright, Lois L.</creatorcontrib><title>Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and
13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and
13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.</description><subject>Aldehydes</subject><subject>Aldehydes - chemistry</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Cathepsin K</subject><subject>Cathepsin K inhibitors</subject><subject>Cathepsins - antagonists & inhibitors</subject><subject>Crystallography, X-Ray</subject><subject>Cysteine protease inhibitors</subject><subject>Drug Evaluation, Preclinical</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Hydrolysis</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Pharmacology. Drug treatments</subject><subject>Prodrugs</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacology</subject><subject>Rats</subject><subject>Semicarbazones</subject><subject>Semicarbazones - chemical synthesis</subject><subject>Semicarbazones - chemistry</subject><subject>Semicarbazones - pharmacology</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1rGzEQhkVpaNw0fyCHoktz6jqjtaTVQqGU0KahgR7aQnMSI2k2ltkPR1oH3F-fdWxIT-1pmOF5h5mHsTMBcwFCX6zmrvPtvARQ86eZecFmQmpZLCSol2wGtYbC1PL3MXud8wpASJDyFTsWuqyhXugZu_1BXfSYHP4ZeiocZgo89svo4jikzIeGexyXtM6x59_ec0zEp3bL12kIaXOXeTMkjm2g5TbQX8mPb9hRg22m00M9Yb--fP55-bW4-X51ffnppvBSqLEQujKNFAiuQi8aoUylwsJLJ7D2EDSSRwDvXMDaSG2Uknr61Lja1EGX5eKEne_3ThfdbyiPtovZU9tiT8MmW11pobSQ_wVFJZXRcgeWe9CnIedEjV2n2GHaWgF2Z96u7M683Znfz8wUenvYvnEdhefIQfUEvDsAmD22TcLex_zMVUpVYNTEfdhzNEl7iJRs9pF6TyEm8qMNQ_zXHY-AiaGJ</recordid><startdate>20060215</startdate><enddate>20060215</enddate><creator>Adkison, Kim K.</creator><creator>Barrett, David G.</creator><creator>Deaton, David N.</creator><creator>Gampe, Robert T.</creator><creator>Hassell, Anne M.</creator><creator>Long, Stacey T.</creator><creator>McFadyen, Robert B.</creator><creator>Miller, Aaron B.</creator><creator>Miller, Larry R.</creator><creator>Payne, J. Alan</creator><creator>Shewchuk, Lisa M.</creator><creator>Wells-Knecht, Kevin J.</creator><creator>Willard, Derril H.</creator><creator>Wright, Lois L.</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20060215</creationdate><title>Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?</title><author>Adkison, Kim K. ; Barrett, David G. ; Deaton, David N. ; Gampe, Robert T. ; Hassell, Anne M. ; Long, Stacey T. ; McFadyen, Robert B. ; Miller, Aaron B. ; Miller, Larry R. ; Payne, J. 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Antiinflammatory agents</topic><topic>Cathepsin K</topic><topic>Cathepsin K inhibitors</topic><topic>Cathepsins - antagonists & inhibitors</topic><topic>Crystallography, X-Ray</topic><topic>Cysteine protease inhibitors</topic><topic>Drug Evaluation, Preclinical</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Hydrolysis</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Pharmacology. Drug treatments</topic><topic>Prodrugs</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - pharmacology</topic><topic>Rats</topic><topic>Semicarbazones</topic><topic>Semicarbazones - chemical synthesis</topic><topic>Semicarbazones - chemistry</topic><topic>Semicarbazones - pharmacology</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Adkison, Kim K.</creatorcontrib><creatorcontrib>Barrett, David G.</creatorcontrib><creatorcontrib>Deaton, David N.</creatorcontrib><creatorcontrib>Gampe, Robert T.</creatorcontrib><creatorcontrib>Hassell, Anne M.</creatorcontrib><creatorcontrib>Long, Stacey T.</creatorcontrib><creatorcontrib>McFadyen, Robert B.</creatorcontrib><creatorcontrib>Miller, Aaron B.</creatorcontrib><creatorcontrib>Miller, Larry R.</creatorcontrib><creatorcontrib>Payne, J. 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Alan</au><au>Shewchuk, Lisa M.</au><au>Wells-Knecht, Kevin J.</au><au>Willard, Derril H.</au><au>Wright, Lois L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2006-02-15</date><risdate>2006</risdate><volume>16</volume><issue>4</issue><spage>978</spage><epage>983</epage><pages>978-983</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and
13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and
13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>16290936</pmid><doi>10.1016/j.bmcl.2005.10.108</doi><tpages>6</tpages></addata></record> |
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| subjects | Aldehydes Aldehydes - chemistry Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cathepsin K Cathepsin K inhibitors Cathepsins - antagonists & inhibitors Crystallography, X-Ray Cysteine protease inhibitors Drug Evaluation, Preclinical Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Hydrogen-Ion Concentration Hydrolysis Medical sciences Models, Molecular Molecular Conformation Pharmacology. Drug treatments Prodrugs Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacology Rats Semicarbazones Semicarbazones - chemical synthesis Semicarbazones - chemistry Semicarbazones - pharmacology Solubility Structure-Activity Relationship |
| title | Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors? |
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