Synthesis and Antibacterial Activity of Novel C12 Vinyl Ketolides
A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C1...
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| Veröffentlicht in: | Journal of medicinal chemistry 2006-03, Vol.49 (5), p.1730-1743 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 49 |
| creator | Burger, Matthew T Lin, Xiaodong Chu, Daniel T Hiebert, Christy Rico, Alice C Seid, Mehran Carroll, Georgia L Barker, Lynn Huh, Kay Langhorne, Mike Shawar, Ribhi Kidney, Jolene Young, Kelly Anderson, Scott Desai, Manoj C Plattner, Jacob J |
| description | A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae. |
| doi_str_mv | 10.1021/jm051157a |
| format | Article |
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The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm051157a</identifier><identifier>PMID: 16509588</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - pharmacokinetics ; Anti-Bacterial Agents - pharmacology ; Biological Availability ; Drug Resistance, Bacterial ; Enterococcus faecalis - drug effects ; Haemophilus Infections - drug therapy ; Haemophilus influenzae - drug effects ; Half-Life ; Ketolides - chemical synthesis ; Ketolides - pharmacokinetics ; Ketolides - pharmacology ; Lung Diseases - drug therapy ; Lung Diseases - microbiology ; Male ; Microbial Sensitivity Tests ; Pneumococcal Infections - drug therapy ; Rats ; Rats, Sprague-Dawley ; Staphylococcus aureus - drug effects ; Streptococcus pneumoniae - drug effects ; Streptococcus pyogenes - drug effects ; Structure-Activity Relationship ; Vinyl Compounds - chemical synthesis ; Vinyl Compounds - pharmacokinetics ; Vinyl Compounds - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2006-03, Vol.49 (5), p.1730-1743</ispartof><rights>Copyright © 2006 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm051157a$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm051157a$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16509588$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Burger, Matthew T</creatorcontrib><creatorcontrib>Lin, Xiaodong</creatorcontrib><creatorcontrib>Chu, Daniel T</creatorcontrib><creatorcontrib>Hiebert, Christy</creatorcontrib><creatorcontrib>Rico, Alice C</creatorcontrib><creatorcontrib>Seid, Mehran</creatorcontrib><creatorcontrib>Carroll, Georgia L</creatorcontrib><creatorcontrib>Barker, Lynn</creatorcontrib><creatorcontrib>Huh, Kay</creatorcontrib><creatorcontrib>Langhorne, Mike</creatorcontrib><creatorcontrib>Shawar, Ribhi</creatorcontrib><creatorcontrib>Kidney, Jolene</creatorcontrib><creatorcontrib>Young, Kelly</creatorcontrib><creatorcontrib>Anderson, Scott</creatorcontrib><creatorcontrib>Desai, Manoj C</creatorcontrib><creatorcontrib>Plattner, Jacob J</creatorcontrib><title>Synthesis and Antibacterial Activity of Novel C12 Vinyl Ketolides</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.</description><subject>Animals</subject><subject>Anti-Bacterial Agents - chemical synthesis</subject><subject>Anti-Bacterial Agents - pharmacokinetics</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Biological Availability</subject><subject>Drug Resistance, Bacterial</subject><subject>Enterococcus faecalis - drug effects</subject><subject>Haemophilus Infections - drug therapy</subject><subject>Haemophilus influenzae - drug effects</subject><subject>Half-Life</subject><subject>Ketolides - chemical synthesis</subject><subject>Ketolides - pharmacokinetics</subject><subject>Ketolides - pharmacology</subject><subject>Lung Diseases - drug therapy</subject><subject>Lung Diseases - microbiology</subject><subject>Male</subject><subject>Microbial Sensitivity Tests</subject><subject>Pneumococcal Infections - drug therapy</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Staphylococcus aureus - drug effects</subject><subject>Streptococcus pneumoniae - drug effects</subject><subject>Streptococcus pyogenes - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>Vinyl Compounds - chemical synthesis</subject><subject>Vinyl Compounds - pharmacokinetics</subject><subject>Vinyl Compounds - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo90MFOwkAQBuCN0QiiB1_A9KK36szutluOhCgYCEpArpttO8TF0mJ3IfL21oAkk8xhvvzJ_IzdIjwicHxarSFCjJQ5Y22MOIQyAXnO2gCchzzmosWunFsBgEAuLlkL4wi6UZK0WW-2L_0nOesCU-ZBr_Q2NZmn2poi6GXe7qzfB9UymFQ7KoI-8mBhy30RjMhXhc3JXbOLpSkc3Rx3h328PM_7w3D8Nnjt98ahwS73oeJyCYpDJslQhDKWcY6xSYBiKQWmiUozgwa6QqbLNJEJSZFLpQhEqgyR6LCHQ-6mrr635LxeW5dRUZiSqq3TsVIIzTTw7gi36Zpyvant2tR7_f90A8IDsM7Tz-lu6q8mRKhIz99nWg6nIxwsJnra-PuDN5nTq2pbl82fGkH_la9P5YtfcYRxgg</recordid><startdate>20060309</startdate><enddate>20060309</enddate><creator>Burger, Matthew T</creator><creator>Lin, Xiaodong</creator><creator>Chu, Daniel T</creator><creator>Hiebert, Christy</creator><creator>Rico, Alice C</creator><creator>Seid, Mehran</creator><creator>Carroll, Georgia L</creator><creator>Barker, Lynn</creator><creator>Huh, Kay</creator><creator>Langhorne, Mike</creator><creator>Shawar, Ribhi</creator><creator>Kidney, Jolene</creator><creator>Young, Kelly</creator><creator>Anderson, Scott</creator><creator>Desai, Manoj C</creator><creator>Plattner, Jacob J</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20060309</creationdate><title>Synthesis and Antibacterial Activity of Novel C12 Vinyl Ketolides</title><author>Burger, Matthew T ; Lin, Xiaodong ; Chu, Daniel T ; Hiebert, Christy ; Rico, Alice C ; Seid, Mehran ; Carroll, Georgia L ; Barker, Lynn ; Huh, Kay ; Langhorne, Mike ; Shawar, Ribhi ; Kidney, Jolene ; Young, Kelly ; Anderson, Scott ; Desai, Manoj C ; Plattner, Jacob J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a192t-724f0720c4eae514646d16a80e64431b87bca1a0934bfb848e43d477e03b7aee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Anti-Bacterial Agents - chemical synthesis</topic><topic>Anti-Bacterial Agents - pharmacokinetics</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Biological Availability</topic><topic>Drug Resistance, Bacterial</topic><topic>Enterococcus faecalis - drug effects</topic><topic>Haemophilus Infections - drug therapy</topic><topic>Haemophilus influenzae - drug effects</topic><topic>Half-Life</topic><topic>Ketolides - chemical synthesis</topic><topic>Ketolides - pharmacokinetics</topic><topic>Ketolides - pharmacology</topic><topic>Lung Diseases - drug therapy</topic><topic>Lung Diseases - microbiology</topic><topic>Male</topic><topic>Microbial Sensitivity Tests</topic><topic>Pneumococcal Infections - drug therapy</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Staphylococcus aureus - drug effects</topic><topic>Streptococcus pneumoniae - drug effects</topic><topic>Streptococcus pyogenes - drug effects</topic><topic>Structure-Activity Relationship</topic><topic>Vinyl Compounds - chemical synthesis</topic><topic>Vinyl Compounds - pharmacokinetics</topic><topic>Vinyl Compounds - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Burger, Matthew T</creatorcontrib><creatorcontrib>Lin, Xiaodong</creatorcontrib><creatorcontrib>Chu, Daniel T</creatorcontrib><creatorcontrib>Hiebert, Christy</creatorcontrib><creatorcontrib>Rico, Alice C</creatorcontrib><creatorcontrib>Seid, Mehran</creatorcontrib><creatorcontrib>Carroll, Georgia L</creatorcontrib><creatorcontrib>Barker, Lynn</creatorcontrib><creatorcontrib>Huh, Kay</creatorcontrib><creatorcontrib>Langhorne, Mike</creatorcontrib><creatorcontrib>Shawar, Ribhi</creatorcontrib><creatorcontrib>Kidney, Jolene</creatorcontrib><creatorcontrib>Young, Kelly</creatorcontrib><creatorcontrib>Anderson, Scott</creatorcontrib><creatorcontrib>Desai, Manoj C</creatorcontrib><creatorcontrib>Plattner, Jacob J</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Burger, Matthew T</au><au>Lin, Xiaodong</au><au>Chu, Daniel T</au><au>Hiebert, Christy</au><au>Rico, Alice C</au><au>Seid, Mehran</au><au>Carroll, Georgia L</au><au>Barker, Lynn</au><au>Huh, Kay</au><au>Langhorne, Mike</au><au>Shawar, Ribhi</au><au>Kidney, Jolene</au><au>Young, Kelly</au><au>Anderson, Scott</au><au>Desai, Manoj C</au><au>Plattner, Jacob J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Antibacterial Activity of Novel C12 Vinyl Ketolides</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2006-03-09</date><risdate>2006</risdate><volume>49</volume><issue>5</issue><spage>1730</spage><epage>1743</epage><pages>1730-1743</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>16509588</pmid><doi>10.1021/jm051157a</doi><tpages>14</tpages></addata></record> |
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| source | MEDLINE; American Chemical Society Publications |
| subjects | Animals Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - pharmacokinetics Anti-Bacterial Agents - pharmacology Biological Availability Drug Resistance, Bacterial Enterococcus faecalis - drug effects Haemophilus Infections - drug therapy Haemophilus influenzae - drug effects Half-Life Ketolides - chemical synthesis Ketolides - pharmacokinetics Ketolides - pharmacology Lung Diseases - drug therapy Lung Diseases - microbiology Male Microbial Sensitivity Tests Pneumococcal Infections - drug therapy Rats Rats, Sprague-Dawley Staphylococcus aureus - drug effects Streptococcus pneumoniae - drug effects Streptococcus pyogenes - drug effects Structure-Activity Relationship Vinyl Compounds - chemical synthesis Vinyl Compounds - pharmacokinetics Vinyl Compounds - pharmacology |
| title | Synthesis and Antibacterial Activity of Novel C12 Vinyl Ketolides |
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