Discovery of N-{N-[(3-Cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(l)-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-(l)-phenylalanine (MK-0668), an Extremely Potent and Orally Active Antagonist of Very Late Antigen-4
Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2009-06, Vol.52 (11), p.3449-3452 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3452 |
|---|---|
| container_issue | 11 |
| container_start_page | 3449 |
| container_title | Journal of medicinal chemistry |
| container_volume | 52 |
| creator | Lin, Linus S Lanza, Thomas Jewell, James P Liu, Ping Jones, Carrie Kieczykowski, Gerard R Treonze, Kelly Si, Qian Manior, Salony Koo, Gloria Tong, Xinchun Wang, Junying Schuelke, Anne Pivnichny, James Wang, Regina Raab, Conrad Vincent, Stella Davies, Philip MacCoss, Malcolm Mumford, Richard A Hagmann, William K |
| description | Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing. |
| doi_str_mv | 10.1021/jm900257b |
| format | Article |
| fullrecord | <record><control><sourceid>acs_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1021_jm900257b</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>b531563903</sourcerecordid><originalsourceid>FETCH-LOGICAL-a343t-a451234466440f02b6c56cadfe5e00848473d4aaeccdd7d08a776144546613243</originalsourceid><addsrcrecordid>eNptkc9uEzEQxi0EoqFw4AXQXpCyUg22d3azOUZpC4jQIgRcULWaeL2tI68d2U7FqkLimXgeTjwJzh-VCxfb-vT75pvxEPKcs1ecCf561U8ZE-Vk-YCMeCkYhZrBQzJKoqCiEsUReRLCijFWcFE8Jkd8CsBrPh2R36c6SHer_JC5Lrugdxf027ig8wGtW98oO5g8bEzn0uOKwvhTTuUgjVtu4mCw19bRscnp2jszmB8UtuY_P3-dlOmgrZY3xnmng7NaupjoVG7nutrbdgFo0GqrsvGH95RVVZ2fZGizs-_Rq16ZIfvoorIxaW126dEkZSajvlXZzEa8TqVD3Pb-dTvDAuNO19fKUnhKHnVognp2uI_Jl_Ozz_O3dHH55t18tqBYQBEpQpm-BaCqAFjHxLKSZSWx7VSpGKuhhknRAqKSsm0nLatxMqk4QJkcvBBQHJN8X1d6F4JXXbP2ukc_NJw12w019xtK7Is9u94se9X-Iw8rScDLA4BBouk8WqnDPSd4xct96IFDGZqV23ibRvxP4F8-c6bL</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Discovery of N-{N-[(3-Cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(l)-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-(l)-phenylalanine (MK-0668), an Extremely Potent and Orally Active Antagonist of Very Late Antigen-4</title><source>ACS Publications</source><source>MEDLINE</source><creator>Lin, Linus S ; Lanza, Thomas ; Jewell, James P ; Liu, Ping ; Jones, Carrie ; Kieczykowski, Gerard R ; Treonze, Kelly ; Si, Qian ; Manior, Salony ; Koo, Gloria ; Tong, Xinchun ; Wang, Junying ; Schuelke, Anne ; Pivnichny, James ; Wang, Regina ; Raab, Conrad ; Vincent, Stella ; Davies, Philip ; MacCoss, Malcolm ; Mumford, Richard A ; Hagmann, William K</creator><creatorcontrib>Lin, Linus S ; Lanza, Thomas ; Jewell, James P ; Liu, Ping ; Jones, Carrie ; Kieczykowski, Gerard R ; Treonze, Kelly ; Si, Qian ; Manior, Salony ; Koo, Gloria ; Tong, Xinchun ; Wang, Junying ; Schuelke, Anne ; Pivnichny, James ; Wang, Regina ; Raab, Conrad ; Vincent, Stella ; Davies, Philip ; MacCoss, Malcolm ; Mumford, Richard A ; Hagmann, William K</creatorcontrib><description>Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm900257b</identifier><identifier>PMID: 19441819</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Administration, Oral ; Animals ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Cytochrome P-450 CYP3A ; Cytochrome P-450 CYP3A Inhibitors ; Dogs ; Humans ; Inhibitory Concentration 50 ; Integrin alpha4beta1 - antagonists & inhibitors ; Medical sciences ; Niacinamide - analogs & derivatives ; Niacinamide - chemical synthesis ; Niacinamide - pharmacokinetics ; Niacinamide - pharmacology ; Pharmacology. Drug treatments ; Phenylalanine - administration & dosage ; Phenylalanine - analogs & derivatives ; Phenylalanine - chemical synthesis ; Phenylalanine - pharmacokinetics ; Phenylalanine - pharmacology ; Rats</subject><ispartof>Journal of medicinal chemistry, 2009-06, Vol.52 (11), p.3449-3452</ispartof><rights>Copyright © 2009 American Chemical Society</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a343t-a451234466440f02b6c56cadfe5e00848473d4aaeccdd7d08a776144546613243</citedby><cites>FETCH-LOGICAL-a343t-a451234466440f02b6c56cadfe5e00848473d4aaeccdd7d08a776144546613243</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm900257b$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm900257b$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21615324$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19441819$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lin, Linus S</creatorcontrib><creatorcontrib>Lanza, Thomas</creatorcontrib><creatorcontrib>Jewell, James P</creatorcontrib><creatorcontrib>Liu, Ping</creatorcontrib><creatorcontrib>Jones, Carrie</creatorcontrib><creatorcontrib>Kieczykowski, Gerard R</creatorcontrib><creatorcontrib>Treonze, Kelly</creatorcontrib><creatorcontrib>Si, Qian</creatorcontrib><creatorcontrib>Manior, Salony</creatorcontrib><creatorcontrib>Koo, Gloria</creatorcontrib><creatorcontrib>Tong, Xinchun</creatorcontrib><creatorcontrib>Wang, Junying</creatorcontrib><creatorcontrib>Schuelke, Anne</creatorcontrib><creatorcontrib>Pivnichny, James</creatorcontrib><creatorcontrib>Wang, Regina</creatorcontrib><creatorcontrib>Raab, Conrad</creatorcontrib><creatorcontrib>Vincent, Stella</creatorcontrib><creatorcontrib>Davies, Philip</creatorcontrib><creatorcontrib>MacCoss, Malcolm</creatorcontrib><creatorcontrib>Mumford, Richard A</creatorcontrib><creatorcontrib>Hagmann, William K</creatorcontrib><title>Discovery of N-{N-[(3-Cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(l)-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-(l)-phenylalanine (MK-0668), an Extremely Potent and Orally Active Antagonist of Very Late Antigen-4</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Cytochrome P-450 CYP3A</subject><subject>Cytochrome P-450 CYP3A Inhibitors</subject><subject>Dogs</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Integrin alpha4beta1 - antagonists & inhibitors</subject><subject>Medical sciences</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Niacinamide - chemical synthesis</subject><subject>Niacinamide - pharmacokinetics</subject><subject>Niacinamide - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenylalanine - administration & dosage</subject><subject>Phenylalanine - analogs & derivatives</subject><subject>Phenylalanine - chemical synthesis</subject><subject>Phenylalanine - pharmacokinetics</subject><subject>Phenylalanine - pharmacology</subject><subject>Rats</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc9uEzEQxi0EoqFw4AXQXpCyUg22d3azOUZpC4jQIgRcULWaeL2tI68d2U7FqkLimXgeTjwJzh-VCxfb-vT75pvxEPKcs1ecCf561U8ZE-Vk-YCMeCkYhZrBQzJKoqCiEsUReRLCijFWcFE8Jkd8CsBrPh2R36c6SHer_JC5Lrugdxf027ig8wGtW98oO5g8bEzn0uOKwvhTTuUgjVtu4mCw19bRscnp2jszmB8UtuY_P3-dlOmgrZY3xnmng7NaupjoVG7nutrbdgFo0GqrsvGH95RVVZ2fZGizs-_Rq16ZIfvoorIxaW126dEkZSajvlXZzEa8TqVD3Pb-dTvDAuNO19fKUnhKHnVognp2uI_Jl_Ozz_O3dHH55t18tqBYQBEpQpm-BaCqAFjHxLKSZSWx7VSpGKuhhknRAqKSsm0nLatxMqk4QJkcvBBQHJN8X1d6F4JXXbP2ukc_NJw12w019xtK7Is9u94se9X-Iw8rScDLA4BBouk8WqnDPSd4xct96IFDGZqV23ibRvxP4F8-c6bL</recordid><startdate>20090611</startdate><enddate>20090611</enddate><creator>Lin, Linus S</creator><creator>Lanza, Thomas</creator><creator>Jewell, James P</creator><creator>Liu, Ping</creator><creator>Jones, Carrie</creator><creator>Kieczykowski, Gerard R</creator><creator>Treonze, Kelly</creator><creator>Si, Qian</creator><creator>Manior, Salony</creator><creator>Koo, Gloria</creator><creator>Tong, Xinchun</creator><creator>Wang, Junying</creator><creator>Schuelke, Anne</creator><creator>Pivnichny, James</creator><creator>Wang, Regina</creator><creator>Raab, Conrad</creator><creator>Vincent, Stella</creator><creator>Davies, Philip</creator><creator>MacCoss, Malcolm</creator><creator>Mumford, Richard A</creator><creator>Hagmann, William K</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>20090611</creationdate><title>Discovery of N-{N-[(3-Cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(l)-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-(l)-phenylalanine (MK-0668), an Extremely Potent and Orally Active Antagonist of Very Late Antigen-4</title><author>Lin, Linus S ; Lanza, Thomas ; Jewell, James P ; Liu, Ping ; Jones, Carrie ; Kieczykowski, Gerard R ; Treonze, Kelly ; Si, Qian ; Manior, Salony ; Koo, Gloria ; Tong, Xinchun ; Wang, Junying ; Schuelke, Anne ; Pivnichny, James ; Wang, Regina ; Raab, Conrad ; Vincent, Stella ; Davies, Philip ; MacCoss, Malcolm ; Mumford, Richard A ; Hagmann, William K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a343t-a451234466440f02b6c56cadfe5e00848473d4aaeccdd7d08a776144546613243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Cytochrome P-450 CYP3A</topic><topic>Cytochrome P-450 CYP3A Inhibitors</topic><topic>Dogs</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Integrin alpha4beta1 - antagonists & inhibitors</topic><topic>Medical sciences</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Niacinamide - chemical synthesis</topic><topic>Niacinamide - pharmacokinetics</topic><topic>Niacinamide - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenylalanine - administration & dosage</topic><topic>Phenylalanine - analogs & derivatives</topic><topic>Phenylalanine - chemical synthesis</topic><topic>Phenylalanine - pharmacokinetics</topic><topic>Phenylalanine - pharmacology</topic><topic>Rats</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lin, Linus S</creatorcontrib><creatorcontrib>Lanza, Thomas</creatorcontrib><creatorcontrib>Jewell, James P</creatorcontrib><creatorcontrib>Liu, Ping</creatorcontrib><creatorcontrib>Jones, Carrie</creatorcontrib><creatorcontrib>Kieczykowski, Gerard R</creatorcontrib><creatorcontrib>Treonze, Kelly</creatorcontrib><creatorcontrib>Si, Qian</creatorcontrib><creatorcontrib>Manior, Salony</creatorcontrib><creatorcontrib>Koo, Gloria</creatorcontrib><creatorcontrib>Tong, Xinchun</creatorcontrib><creatorcontrib>Wang, Junying</creatorcontrib><creatorcontrib>Schuelke, Anne</creatorcontrib><creatorcontrib>Pivnichny, James</creatorcontrib><creatorcontrib>Wang, Regina</creatorcontrib><creatorcontrib>Raab, Conrad</creatorcontrib><creatorcontrib>Vincent, Stella</creatorcontrib><creatorcontrib>Davies, Philip</creatorcontrib><creatorcontrib>MacCoss, Malcolm</creatorcontrib><creatorcontrib>Mumford, Richard A</creatorcontrib><creatorcontrib>Hagmann, William K</creatorcontrib><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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lin, Linus S</au><au>Lanza, Thomas</au><au>Jewell, James P</au><au>Liu, Ping</au><au>Jones, Carrie</au><au>Kieczykowski, Gerard R</au><au>Treonze, Kelly</au><au>Si, Qian</au><au>Manior, Salony</au><au>Koo, Gloria</au><au>Tong, Xinchun</au><au>Wang, Junying</au><au>Schuelke, Anne</au><au>Pivnichny, James</au><au>Wang, Regina</au><au>Raab, Conrad</au><au>Vincent, Stella</au><au>Davies, Philip</au><au>MacCoss, Malcolm</au><au>Mumford, Richard A</au><au>Hagmann, William K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of N-{N-[(3-Cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(l)-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-(l)-phenylalanine (MK-0668), an Extremely Potent and Orally Active Antagonist of Very Late Antigen-4</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2009-06-11</date><risdate>2009</risdate><volume>52</volume><issue>11</issue><spage>3449</spage><epage>3452</epage><pages>3449-3452</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19441819</pmid><doi>10.1021/jm900257b</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2009-06, Vol.52 (11), p.3449-3452 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_jm900257b |
| source | ACS Publications; MEDLINE |
| subjects | Administration, Oral Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cytochrome P-450 CYP3A Cytochrome P-450 CYP3A Inhibitors Dogs Humans Inhibitory Concentration 50 Integrin alpha4beta1 - antagonists & inhibitors Medical sciences Niacinamide - analogs & derivatives Niacinamide - chemical synthesis Niacinamide - pharmacokinetics Niacinamide - pharmacology Pharmacology. Drug treatments Phenylalanine - administration & dosage Phenylalanine - analogs & derivatives Phenylalanine - chemical synthesis Phenylalanine - pharmacokinetics Phenylalanine - pharmacology Rats |
| title | Discovery of N-{N-[(3-Cyanophenyl)sulfonyl]-4(R)-cyclobutylamino-(l)-prolyl}-4-[(3′,5′-dichloroisonicotinoyl)amino]-(l)-phenylalanine (MK-0668), an Extremely Potent and Orally Active Antagonist of Very Late Antigen-4 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T06%3A50%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-acs_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%20N-%7BN-%5B(3-Cyanophenyl)sulfonyl%5D-4(R)-cyclobutylamino-(l)-prolyl%7D-4-%5B(3%E2%80%B2,5%E2%80%B2-dichloroisonicotinoyl)amino%5D-(l)-phenylalanine%20(MK-0668),%20an%20Extremely%20Potent%20and%20Orally%20Active%20Antagonist%20of%20Very%20Late%20Antigen-4&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Lin,%20Linus%20S&rft.date=2009-06-11&rft.volume=52&rft.issue=11&rft.spage=3449&rft.epage=3452&rft.pages=3449-3452&rft.issn=0022-2623&rft.eissn=1520-4804&rft.coden=JMCMAR&rft_id=info:doi/10.1021/jm900257b&rft_dat=%3Cacs_cross%3Eb531563903%3C/acs_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/19441819&rfr_iscdi=true |