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Potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme identified in rat lung
Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed. Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series. Alternatively,...
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| Published in: | Journal of medicinal chemistry 1993-02, Vol.36 (4), p.468-478 |
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| Main Authors: | , , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-a383t-9e93ddf4794e5e7de435dbeb40e0cca744352385362b0d5d846e63df7f5516933 |
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| container_end_page | 478 |
| container_issue | 4 |
| container_start_page | 468 |
| container_title | Journal of medicinal chemistry |
| container_volume | 36 |
| creator | Shiosaki, Kazumi Tasker, Andrew S Sullivan, Gerard M Sorensen, Bryan K von Geldern, Thomas W Wu-Wong, Jinshyun R Marselle, Carol A Opgenorth, Terry J |
| description | Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed. Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series. Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity. Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity. Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D. Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing. Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors. |
| doi_str_mv | 10.1021/jm00056a007 |
| format | article |
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Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series. Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity. Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity. Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D. Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing. Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00056a007</identifier><identifier>PMID: 8474103</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Amino Acid Sequence ; Amino Acids - chemistry ; Analytical, structural and metabolic biochemistry ; Animals ; Aspartic Acid Endopeptidases - antagonists & inhibitors ; Biological and medical sciences ; Blood Pressure - drug effects ; Cathepsin D - antagonists & inhibitors ; Cell Membrane - enzymology ; Endothelin-Converting Enzymes ; Endothelins - metabolism ; Enzymes and enzyme inhibitors ; Fundamental and applied biological sciences. Psychology ; Humans ; Hydrolases ; Lung - enzymology ; Metalloendopeptidases ; Molecular Sequence Data ; Molecular Structure ; Pepstatins - chemistry ; Pepstatins - pharmacology ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Rats ; Renin - antagonists & inhibitors ; Solubility ; Structure-Activity Relationship ; Water</subject><ispartof>Journal of medicinal chemistry, 1993-02, Vol.36 (4), p.468-478</ispartof><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a383t-9e93ddf4794e5e7de435dbeb40e0cca744352385362b0d5d846e63df7f5516933</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00056a007$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00056a007$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,783,787,27077,27937,27938,57099,57149</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4662622$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8474103$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shiosaki, Kazumi</creatorcontrib><creatorcontrib>Tasker, Andrew S</creatorcontrib><creatorcontrib>Sullivan, Gerard M</creatorcontrib><creatorcontrib>Sorensen, Bryan K</creatorcontrib><creatorcontrib>von Geldern, Thomas W</creatorcontrib><creatorcontrib>Wu-Wong, Jinshyun R</creatorcontrib><creatorcontrib>Marselle, Carol A</creatorcontrib><creatorcontrib>Opgenorth, Terry J</creatorcontrib><title>Potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme identified in rat lung</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed. Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series. Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity. Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity. Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D. Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing. Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors.</description><subject>Amino Acid Sequence</subject><subject>Amino Acids - chemistry</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>Aspartic Acid Endopeptidases - antagonists & inhibitors</subject><subject>Biological and medical sciences</subject><subject>Blood Pressure - drug effects</subject><subject>Cathepsin D - antagonists & inhibitors</subject><subject>Cell Membrane - enzymology</subject><subject>Endothelin-Converting Enzymes</subject><subject>Endothelins - metabolism</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Hydrolases</subject><subject>Lung - enzymology</subject><subject>Metalloendopeptidases</subject><subject>Molecular Sequence Data</subject><subject>Molecular Structure</subject><subject>Pepstatins - chemistry</subject><subject>Pepstatins - pharmacology</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Rats</subject><subject>Renin - antagonists & inhibitors</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><subject>Water</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1993</creationdate><recordtype>article</recordtype><recordid>eNptkc9rFDEUx4NY6lo9eRZyED3I1Ex-zhylaBUKXWgFbyGTvGmzzWTWJFNc_3pTdlk8eAov3w_f9-X7EHrTkvOW0PbTZiKECGkIUc_QqhWUNLwj_DlaEUJpQyVlL9DLnDcVYy1lp-i044q3hK3Qdj0XiAWb6HCGALb4R8A-3vvBlzllPI9VwyZvTSq7gLep8iZDE_wDYIhuLvcQfMR2jo-Qio939ffPbqomrhr70YOrfjiZgsMS716hk9GEDK8P7xn68fXL7cW35ur68vvF56vGsI6VpoeeOTdy1XMQoBxwJtwAAydArDWK15myTjBJB-KE67gEydyoRiFa2TN2ht7vfWviXwvkoiefLYRgIsxL1kpIVcugFfy4B22ac04w6m3yk0k73RL91K_-p99Kvz3YLsME7sgeCq36u4NusjVhTCZan48Yl7Ke42lps8d8LvD7KJv0oGssJfTt-kb3a_GTX1KuReU_7Hljs97MS4q1u_8G_Au8NJ8L</recordid><startdate>19930219</startdate><enddate>19930219</enddate><creator>Shiosaki, Kazumi</creator><creator>Tasker, Andrew S</creator><creator>Sullivan, Gerard M</creator><creator>Sorensen, Bryan K</creator><creator>von Geldern, Thomas W</creator><creator>Wu-Wong, Jinshyun R</creator><creator>Marselle, Carol A</creator><creator>Opgenorth, Terry J</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>19930219</creationdate><title>Potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme identified in rat lung</title><author>Shiosaki, Kazumi ; Tasker, Andrew S ; Sullivan, Gerard M ; Sorensen, Bryan K ; von Geldern, Thomas W ; Wu-Wong, Jinshyun R ; Marselle, Carol A ; Opgenorth, Terry J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a383t-9e93ddf4794e5e7de435dbeb40e0cca744352385362b0d5d846e63df7f5516933</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1993</creationdate><topic>Amino Acid Sequence</topic><topic>Amino Acids - chemistry</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Animals</topic><topic>Aspartic Acid Endopeptidases - antagonists & inhibitors</topic><topic>Biological and medical sciences</topic><topic>Blood Pressure - drug effects</topic><topic>Cathepsin D - antagonists & inhibitors</topic><topic>Cell Membrane - enzymology</topic><topic>Endothelin-Converting Enzymes</topic><topic>Endothelins - metabolism</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Humans</topic><topic>Hydrolases</topic><topic>Lung - enzymology</topic><topic>Metalloendopeptidases</topic><topic>Molecular Sequence Data</topic><topic>Molecular Structure</topic><topic>Pepstatins - chemistry</topic><topic>Pepstatins - pharmacology</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Rats</topic><topic>Renin - antagonists & inhibitors</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><topic>Water</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shiosaki, Kazumi</creatorcontrib><creatorcontrib>Tasker, Andrew S</creatorcontrib><creatorcontrib>Sullivan, Gerard M</creatorcontrib><creatorcontrib>Sorensen, Bryan K</creatorcontrib><creatorcontrib>von Geldern, Thomas W</creatorcontrib><creatorcontrib>Wu-Wong, Jinshyun R</creatorcontrib><creatorcontrib>Marselle, Carol A</creatorcontrib><creatorcontrib>Opgenorth, Terry J</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>Shiosaki, Kazumi</au><au>Tasker, Andrew S</au><au>Sullivan, Gerard M</au><au>Sorensen, Bryan K</au><au>von Geldern, Thomas W</au><au>Wu-Wong, Jinshyun R</au><au>Marselle, Carol A</au><au>Opgenorth, Terry J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme identified in rat lung</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1993-02-19</date><risdate>1993</risdate><volume>36</volume><issue>4</issue><spage>468</spage><epage>478</epage><pages>468-478</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed. Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series. Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity. Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity. Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D. Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing. Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>8474103</pmid><doi>10.1021/jm00056a007</doi><tpages>11</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1993-02, Vol.36 (4), p.468-478 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | ACS CRKN Legacy Archives |
| subjects | Amino Acid Sequence Amino Acids - chemistry Analytical, structural and metabolic biochemistry Animals Aspartic Acid Endopeptidases - antagonists & inhibitors Biological and medical sciences Blood Pressure - drug effects Cathepsin D - antagonists & inhibitors Cell Membrane - enzymology Endothelin-Converting Enzymes Endothelins - metabolism Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Humans Hydrolases Lung - enzymology Metalloendopeptidases Molecular Sequence Data Molecular Structure Pepstatins - chemistry Pepstatins - pharmacology Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Rats Renin - antagonists & inhibitors Solubility Structure-Activity Relationship Water |
| title | Potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme identified in rat lung |
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