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Structure−Activity Relationships of 9-Substituted-9-Dihydroerythromycin-Based Motilin Agonists: Optimizing for Potency and Safety
A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased...
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| Published in: | Journal of medicinal chemistry 2009-11, Vol.52 (21), p.6851-6859 |
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| Main Authors: | , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-a344t-f6b55c84368d88f333b88e0a415893ec820dc33bcbb10c321506a7b5cae22c63 |
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| cites | cdi_FETCH-LOGICAL-a344t-f6b55c84368d88f333b88e0a415893ec820dc33bcbb10c321506a7b5cae22c63 |
| container_end_page | 6859 |
| container_issue | 21 |
| container_start_page | 6851 |
| container_title | Journal of medicinal chemistry |
| container_volume | 52 |
| creator | Shaw, Simon J Chen, Yue Zheng, Hao Fu, Hong Burlingame, Mark A Marquez, Saul Li, Yong Claypool, Mark Carreras, Christopher W Crumb, William Hardy, Dwight J Myles, David C Liu, Yaoquan |
| description | A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. The N-methyl acetamide 7a showed the optimal in vitro profile and was probed further by varying the chain length to the macrocycle as well as changing the macrocycle scaffold. 7a remained the compound with the best in vitro properties. |
| doi_str_mv | 10.1021/jm901107f |
| format | article |
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The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. The N-methyl acetamide 7a showed the optimal in vitro profile and was probed further by varying the chain length to the macrocycle as well as changing the macrocycle scaffold. 7a remained the compound with the best in vitro properties.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm901107f</identifier><identifier>PMID: 19821563</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Animals ; Antibacterial agents ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Bacteria - drug effects ; Bacteria - isolation & purification ; Biological and medical sciences ; Cell Line ; ERG1 Potassium Channel ; Erythromycin - adverse effects ; Erythromycin - analogs & derivatives ; Erythromycin - chemical synthesis ; Erythromycin - pharmacology ; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors ; Gastrointestinal Agents - adverse effects ; Gastrointestinal Agents - chemical synthesis ; Gastrointestinal Agents - pharmacology ; Humans ; In Vitro Techniques ; Intestines - microbiology ; Medical sciences ; Microbial Sensitivity Tests ; Motilin - agonists ; Muscle Contraction - drug effects ; Muscle, Smooth - drug effects ; Muscle, Smooth - physiology ; Pharmacology. Drug treatments ; Rabbits ; Stereoisomerism ; Structure-Activity Relationship ; Tachyphylaxis</subject><ispartof>Journal of medicinal chemistry, 2009-11, Vol.52 (21), p.6851-6859</ispartof><rights>Copyright © 2009 American Chemical Society</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a344t-f6b55c84368d88f333b88e0a415893ec820dc33bcbb10c321506a7b5cae22c63</citedby><cites>FETCH-LOGICAL-a344t-f6b55c84368d88f333b88e0a415893ec820dc33bcbb10c321506a7b5cae22c63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22108250$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19821563$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shaw, Simon J</creatorcontrib><creatorcontrib>Chen, Yue</creatorcontrib><creatorcontrib>Zheng, Hao</creatorcontrib><creatorcontrib>Fu, Hong</creatorcontrib><creatorcontrib>Burlingame, Mark A</creatorcontrib><creatorcontrib>Marquez, Saul</creatorcontrib><creatorcontrib>Li, Yong</creatorcontrib><creatorcontrib>Claypool, Mark</creatorcontrib><creatorcontrib>Carreras, Christopher W</creatorcontrib><creatorcontrib>Crumb, William</creatorcontrib><creatorcontrib>Hardy, Dwight J</creatorcontrib><creatorcontrib>Myles, David C</creatorcontrib><creatorcontrib>Liu, Yaoquan</creatorcontrib><title>Structure−Activity Relationships of 9-Substituted-9-Dihydroerythromycin-Based Motilin Agonists: Optimizing for Potency and Safety</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. The N-methyl acetamide 7a showed the optimal in vitro profile and was probed further by varying the chain length to the macrocycle as well as changing the macrocycle scaffold. 7a remained the compound with the best in vitro properties.</description><subject>Animals</subject><subject>Antibacterial agents</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Bacteria - drug effects</subject><subject>Bacteria - isolation & purification</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>ERG1 Potassium Channel</subject><subject>Erythromycin - adverse effects</subject><subject>Erythromycin - analogs & derivatives</subject><subject>Erythromycin - chemical synthesis</subject><subject>Erythromycin - pharmacology</subject><subject>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</subject><subject>Gastrointestinal Agents - adverse effects</subject><subject>Gastrointestinal Agents - chemical synthesis</subject><subject>Gastrointestinal Agents - pharmacology</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Intestines - microbiology</subject><subject>Medical sciences</subject><subject>Microbial Sensitivity Tests</subject><subject>Motilin - agonists</subject><subject>Muscle Contraction - drug effects</subject><subject>Muscle, Smooth - drug effects</subject><subject>Muscle, Smooth - physiology</subject><subject>Pharmacology. Drug treatments</subject><subject>Rabbits</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Tachyphylaxis</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNpt0LtKBDEUBuAgiq6XwheQNBYW0ZNkZszYrXdBUVz7IZNJ3Cw7yZJkhLG1sfYRfRJHXLSxOnD4OIf_R2iXwiEFRo9mbQmUwrFZQSOaMyCZgGwVjQAYI6xgfANtxjgDAE4ZX0cbtBSM5gUfobdJCp1KXdCf7x9jleyLTT1-1HOZrHdxahcRe4NLMunqmGzqkm5ISc7ttG-C16FP0-DbXllHTmXUDb7zyc6tw-Nn72xM8QTfL5Jt7at1z9j4gB980k71WLoGT6TRqd9Ga0bOo95Zzi30dHnxdHZNbu-vbs7Gt0TyLEvEFHWeK5HxQjRCGM55LYQGmdFclFwrwaBRw1LVNQXFh4BQyOM6V1Izpgq-hQ5-zqrgYwzaVItgWxn6ikL13WP12-Ng937soqtb3fzJZXED2F8CGZWcmyCdsvHXMUZBsBz-nFSxmvkuuCHhPw-_AJQGigE</recordid><startdate>20091112</startdate><enddate>20091112</enddate><creator>Shaw, Simon J</creator><creator>Chen, Yue</creator><creator>Zheng, Hao</creator><creator>Fu, Hong</creator><creator>Burlingame, Mark A</creator><creator>Marquez, Saul</creator><creator>Li, Yong</creator><creator>Claypool, Mark</creator><creator>Carreras, Christopher W</creator><creator>Crumb, William</creator><creator>Hardy, Dwight J</creator><creator>Myles, David C</creator><creator>Liu, Yaoquan</creator><general>American Chemical Society</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></search><sort><creationdate>20091112</creationdate><title>Structure−Activity Relationships of 9-Substituted-9-Dihydroerythromycin-Based Motilin Agonists: Optimizing for Potency and Safety</title><author>Shaw, Simon J ; Chen, Yue ; Zheng, Hao ; Fu, Hong ; Burlingame, Mark A ; Marquez, Saul ; Li, Yong ; Claypool, Mark ; Carreras, Christopher W ; Crumb, William ; Hardy, Dwight J ; Myles, David C ; Liu, Yaoquan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a344t-f6b55c84368d88f333b88e0a415893ec820dc33bcbb10c321506a7b5cae22c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Antibacterial agents</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Bacteria - drug effects</topic><topic>Bacteria - isolation & purification</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>ERG1 Potassium Channel</topic><topic>Erythromycin - adverse effects</topic><topic>Erythromycin - analogs & derivatives</topic><topic>Erythromycin - chemical synthesis</topic><topic>Erythromycin - pharmacology</topic><topic>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</topic><topic>Gastrointestinal Agents - adverse effects</topic><topic>Gastrointestinal Agents - chemical synthesis</topic><topic>Gastrointestinal Agents - pharmacology</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Intestines - microbiology</topic><topic>Medical sciences</topic><topic>Microbial Sensitivity Tests</topic><topic>Motilin - agonists</topic><topic>Muscle Contraction - drug effects</topic><topic>Muscle, Smooth - drug effects</topic><topic>Muscle, Smooth - physiology</topic><topic>Pharmacology. 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Med. Chem</addtitle><date>2009-11-12</date><risdate>2009</risdate><volume>52</volume><issue>21</issue><spage>6851</spage><epage>6859</epage><pages>6851-6859</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. 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| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2009-11, Vol.52 (21), p.6851-6859 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_jm901107f |
| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Animals Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Bacteria - drug effects Bacteria - isolation & purification Biological and medical sciences Cell Line ERG1 Potassium Channel Erythromycin - adverse effects Erythromycin - analogs & derivatives Erythromycin - chemical synthesis Erythromycin - pharmacology Ether-A-Go-Go Potassium Channels - antagonists & inhibitors Gastrointestinal Agents - adverse effects Gastrointestinal Agents - chemical synthesis Gastrointestinal Agents - pharmacology Humans In Vitro Techniques Intestines - microbiology Medical sciences Microbial Sensitivity Tests Motilin - agonists Muscle Contraction - drug effects Muscle, Smooth - drug effects Muscle, Smooth - physiology Pharmacology. Drug treatments Rabbits Stereoisomerism Structure-Activity Relationship Tachyphylaxis |
| title | Structure−Activity Relationships of 9-Substituted-9-Dihydroerythromycin-Based Motilin Agonists: Optimizing for Potency and Safety |
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