Continued exploration of biphenylsulfonamide scaffold as a platform for aggrecanase-1 inhibition
Biphenylsulfonamido-3-methylbutanoic acids with potent activities in enzymatic and cell-based assays are presented. Design, synthesis and structure–activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggre...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-11, Vol.21 (22), p.6800-6803 |
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| creator | Hu, Yonghan Xing, Li Thomason, Jennifer R. Xiang, Jason Ipek, Manus Guler, Satenig Li, Huanqiu Sabatini, Joshua Chockalingam, Priya Reifenberg, Erica Sheldon, Richard Morris, Elisabeth A. Georgiadis, Katy E. Tam, Steve |
| description | Biphenylsulfonamido-3-methylbutanoic acids with potent activities in enzymatic and cell-based assays are presented.
Design, synthesis and structure–activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound
48 produced 87% inhibition of proteoglycan degradation at 10
μg/mL. Good pharmacokinetic properties were demonstrated by
46 with a half-life of 6
h and bioavailability of 23%. |
| doi_str_mv | 10.1016/j.bmcl.2011.09.036 |
| format | Article |
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Design, synthesis and structure–activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound
48 produced 87% inhibition of proteoglycan degradation at 10
μg/mL. Good pharmacokinetic properties were demonstrated by
46 with a half-life of 6
h and bioavailability of 23%.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.09.036</identifier><identifier>PMID: 21982494</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>ADAM Proteins - antagonists & inhibitors ; ADAM Proteins - metabolism ; ADAMTS4 Protein ; Aggrecanase-1 ; Animals ; bioavailability ; Biological and medical sciences ; Biphenyl Compounds - chemistry ; Biphenyl Compounds - pharmacokinetics ; Biphenyl Compounds - pharmacology ; Biphenylsulfonamide ; cartilage ; Drug Design ; explants ; half life ; Humans ; Male ; Matrix Metalloproteinase 13 - metabolism ; Medical sciences ; MMP-13 ; Models, Molecular ; Osteoarthritis ; Osteoarthritis - drug therapy ; pharmacokinetics ; Pharmacology. Drug treatments ; Procollagen N-Endopeptidase - antagonists & inhibitors ; Procollagen N-Endopeptidase - metabolism ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacokinetics ; Protease Inhibitors - pharmacology ; proteoglycans ; Proteoglycans - metabolism ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; structure-activity relationships ; Sulfonamides - chemistry ; Sulfonamides - pharmacokinetics ; Sulfonamides - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-11, Vol.21 (22), p.6800-6803</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-c650dea5e4736dd9e4cc56b3edb1093354a03e31149c748d7afb0945282eabc23</citedby><cites>FETCH-LOGICAL-c441t-c650dea5e4736dd9e4cc56b3edb1093354a03e31149c748d7afb0945282eabc23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2011.09.036$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25589655$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21982494$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hu, Yonghan</creatorcontrib><creatorcontrib>Xing, Li</creatorcontrib><creatorcontrib>Thomason, Jennifer R.</creatorcontrib><creatorcontrib>Xiang, Jason</creatorcontrib><creatorcontrib>Ipek, Manus</creatorcontrib><creatorcontrib>Guler, Satenig</creatorcontrib><creatorcontrib>Li, Huanqiu</creatorcontrib><creatorcontrib>Sabatini, Joshua</creatorcontrib><creatorcontrib>Chockalingam, Priya</creatorcontrib><creatorcontrib>Reifenberg, Erica</creatorcontrib><creatorcontrib>Sheldon, Richard</creatorcontrib><creatorcontrib>Morris, Elisabeth A.</creatorcontrib><creatorcontrib>Georgiadis, Katy E.</creatorcontrib><creatorcontrib>Tam, Steve</creatorcontrib><title>Continued exploration of biphenylsulfonamide scaffold as a platform for aggrecanase-1 inhibition</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Biphenylsulfonamido-3-methylbutanoic acids with potent activities in enzymatic and cell-based assays are presented.
Design, synthesis and structure–activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound
48 produced 87% inhibition of proteoglycan degradation at 10
μg/mL. Good pharmacokinetic properties were demonstrated by
46 with a half-life of 6
h and bioavailability of 23%.</description><subject>ADAM Proteins - antagonists & inhibitors</subject><subject>ADAM Proteins - metabolism</subject><subject>ADAMTS4 Protein</subject><subject>Aggrecanase-1</subject><subject>Animals</subject><subject>bioavailability</subject><subject>Biological and medical sciences</subject><subject>Biphenyl Compounds - chemistry</subject><subject>Biphenyl Compounds - pharmacokinetics</subject><subject>Biphenyl Compounds - pharmacology</subject><subject>Biphenylsulfonamide</subject><subject>cartilage</subject><subject>Drug Design</subject><subject>explants</subject><subject>half life</subject><subject>Humans</subject><subject>Male</subject><subject>Matrix Metalloproteinase 13 - metabolism</subject><subject>Medical sciences</subject><subject>MMP-13</subject><subject>Models, Molecular</subject><subject>Osteoarthritis</subject><subject>Osteoarthritis - drug therapy</subject><subject>pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Procollagen N-Endopeptidase - antagonists & inhibitors</subject><subject>Procollagen N-Endopeptidase - metabolism</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacokinetics</subject><subject>Protease Inhibitors - pharmacology</subject><subject>proteoglycans</subject><subject>Proteoglycans - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Structure-Activity Relationship</subject><subject>structure-activity relationships</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacokinetics</subject><subject>Sulfonamides - pharmacology</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU-P1CAYhxujcWdXv4AH5WI8tUL5MyXxYia6mmziQTfxhhReZplQqNAa99vLZEa9GS9w4Hl_wO9pmmcEdwQT8frQjZMJXY8J6bDsMBUPmg1hgrWUYf6w2WApcDtI9vWiuSzlgDFhmLHHzUVP5NAzyTbNt12Ki48rWAQ_55CyXnyKKDk0-vkO4n0oa3Ap6slbQMVo51KwSBek0Rz04lKeUF2Q3u8zGB11gZYgH-_86I9RT5pHTocCT8_7VXP7_t2X3Yf25tP1x93bm9YwRpbWCI4taA5sS4W1EpgxXIwU7EiwpJQzjSlQQpg0WzbYrXYjloz3Qw96ND29al6dcuecvq9QFjX5YiAEHSGtRcn6cyn67f-QWPRSElLJ_kSanErJ4NSc_aTzvSJYHRWogzoqUEcFCktVFdSh5-f4dZzA_hn53XkFXp4BXfsMLutofPnLcT5IwXnlXpw4p5PS-1yZ28_1Jl490nouK_HmREAt9oeHrIrxEA1YX10syib_r5f-AnRYrpo</recordid><startdate>20111115</startdate><enddate>20111115</enddate><creator>Hu, Yonghan</creator><creator>Xing, Li</creator><creator>Thomason, Jennifer R.</creator><creator>Xiang, Jason</creator><creator>Ipek, Manus</creator><creator>Guler, Satenig</creator><creator>Li, Huanqiu</creator><creator>Sabatini, Joshua</creator><creator>Chockalingam, Priya</creator><creator>Reifenberg, Erica</creator><creator>Sheldon, Richard</creator><creator>Morris, Elisabeth A.</creator><creator>Georgiadis, Katy E.</creator><creator>Tam, Steve</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20111115</creationdate><title>Continued exploration of biphenylsulfonamide scaffold as a platform for aggrecanase-1 inhibition</title><author>Hu, Yonghan ; Xing, Li ; Thomason, Jennifer R. ; Xiang, Jason ; Ipek, Manus ; Guler, Satenig ; Li, Huanqiu ; Sabatini, Joshua ; Chockalingam, Priya ; Reifenberg, Erica ; Sheldon, Richard ; Morris, Elisabeth A. ; Georgiadis, Katy E. ; Tam, Steve</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-c650dea5e4736dd9e4cc56b3edb1093354a03e31149c748d7afb0945282eabc23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>ADAM Proteins - antagonists & inhibitors</topic><topic>ADAM Proteins - metabolism</topic><topic>ADAMTS4 Protein</topic><topic>Aggrecanase-1</topic><topic>Animals</topic><topic>bioavailability</topic><topic>Biological and medical sciences</topic><topic>Biphenyl Compounds - chemistry</topic><topic>Biphenyl Compounds - pharmacokinetics</topic><topic>Biphenyl Compounds - pharmacology</topic><topic>Biphenylsulfonamide</topic><topic>cartilage</topic><topic>Drug Design</topic><topic>explants</topic><topic>half life</topic><topic>Humans</topic><topic>Male</topic><topic>Matrix Metalloproteinase 13 - metabolism</topic><topic>Medical sciences</topic><topic>MMP-13</topic><topic>Models, Molecular</topic><topic>Osteoarthritis</topic><topic>Osteoarthritis - drug therapy</topic><topic>pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Procollagen N-Endopeptidase - antagonists & inhibitors</topic><topic>Procollagen N-Endopeptidase - metabolism</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacokinetics</topic><topic>Protease Inhibitors - pharmacology</topic><topic>proteoglycans</topic><topic>Proteoglycans - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Structure-Activity Relationship</topic><topic>structure-activity relationships</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacokinetics</topic><topic>Sulfonamides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hu, Yonghan</creatorcontrib><creatorcontrib>Xing, Li</creatorcontrib><creatorcontrib>Thomason, Jennifer R.</creatorcontrib><creatorcontrib>Xiang, Jason</creatorcontrib><creatorcontrib>Ipek, Manus</creatorcontrib><creatorcontrib>Guler, Satenig</creatorcontrib><creatorcontrib>Li, Huanqiu</creatorcontrib><creatorcontrib>Sabatini, Joshua</creatorcontrib><creatorcontrib>Chockalingam, Priya</creatorcontrib><creatorcontrib>Reifenberg, Erica</creatorcontrib><creatorcontrib>Sheldon, Richard</creatorcontrib><creatorcontrib>Morris, Elisabeth A.</creatorcontrib><creatorcontrib>Georgiadis, Katy E.</creatorcontrib><creatorcontrib>Tam, Steve</creatorcontrib><collection>AGRIS</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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hu, Yonghan</au><au>Xing, Li</au><au>Thomason, Jennifer R.</au><au>Xiang, Jason</au><au>Ipek, Manus</au><au>Guler, Satenig</au><au>Li, Huanqiu</au><au>Sabatini, Joshua</au><au>Chockalingam, Priya</au><au>Reifenberg, Erica</au><au>Sheldon, Richard</au><au>Morris, Elisabeth A.</au><au>Georgiadis, Katy E.</au><au>Tam, Steve</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Continued exploration of biphenylsulfonamide scaffold as a platform for aggrecanase-1 inhibition</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-11-15</date><risdate>2011</risdate><volume>21</volume><issue>22</issue><spage>6800</spage><epage>6803</epage><pages>6800-6803</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Biphenylsulfonamido-3-methylbutanoic acids with potent activities in enzymatic and cell-based assays are presented.
Design, synthesis and structure–activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound
48 produced 87% inhibition of proteoglycan degradation at 10
μg/mL. Good pharmacokinetic properties were demonstrated by
46 with a half-life of 6
h and bioavailability of 23%.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21982494</pmid><doi>10.1016/j.bmcl.2011.09.036</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2011-11, Vol.21 (22), p.6800-6803 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_904496272 |
| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | ADAM Proteins - antagonists & inhibitors ADAM Proteins - metabolism ADAMTS4 Protein Aggrecanase-1 Animals bioavailability Biological and medical sciences Biphenyl Compounds - chemistry Biphenyl Compounds - pharmacokinetics Biphenyl Compounds - pharmacology Biphenylsulfonamide cartilage Drug Design explants half life Humans Male Matrix Metalloproteinase 13 - metabolism Medical sciences MMP-13 Models, Molecular Osteoarthritis Osteoarthritis - drug therapy pharmacokinetics Pharmacology. Drug treatments Procollagen N-Endopeptidase - antagonists & inhibitors Procollagen N-Endopeptidase - metabolism Protease Inhibitors - chemistry Protease Inhibitors - pharmacokinetics Protease Inhibitors - pharmacology proteoglycans Proteoglycans - metabolism Rats Rats, Sprague-Dawley Structure-Activity Relationship structure-activity relationships Sulfonamides - chemistry Sulfonamides - pharmacokinetics Sulfonamides - pharmacology |
| title | Continued exploration of biphenylsulfonamide scaffold as a platform for aggrecanase-1 inhibition |
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