Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA)
The discovery, synthesis, and early SAR work on a benzyl amine containing series of uPA inhibitors is reported. In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound 1, a significant change provide...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-10, Vol.19 (19), p.5712-5715 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | West, Christopher W. Adler, Marc Arnaiz, Danny Chen, Deborah Chu, Kieu Gualtieri, Giovanna Ho, Elena Huwe, Christoph Light, David Phillips, Gary Pulk, Rebecca Sukovich, Drew Whitlow, Marc Yuan, Shendong Bryant, Judi |
| description | The discovery, synthesis, and early SAR work on a benzyl amine containing series of uPA inhibitors is reported.
In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound
1, a significant change provided compounds in which the amidine, binding in the S1 pocket, was replaced with a primary amine. Further modifications led to the identification of potent, selective, and orally bioavailable uPA inhibitors. |
| doi_str_mv | 10.1016/j.bmcl.2009.08.008 |
| format | Article |
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In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound
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In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound
1, a significant change provided compounds in which the amidine, binding in the S1 pocket, was replaced with a primary amine. Further modifications led to the identification of potent, selective, and orally bioavailable uPA inhibitors.</description><subject>Administration, Oral</subject><subject>Amidines - chemistry</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>Benzylamines - chemistry</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Crystallography, X-Ray</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Hydrolases</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Serine protease</subject><subject>Serine Proteinase Inhibitors - administration & dosage</subject><subject>Serine Proteinase Inhibitors - chemical synthesis</subject><subject>Serine Proteinase Inhibitors - chemistry</subject><subject>Structure-Activity Relationship</subject><subject>uPA</subject><subject>Urokinase</subject><subject>Urokinase-Type Plasminogen Activator - antagonists & inhibitors</subject><subject>Urokinase-Type Plasminogen Activator - metabolism</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90U1vEzEQBmALgWgI_AEOaC98SWwYf2Q_JC5RVaBSJXqgEjdr1mvDBK_d2ptI_fd1lAhuPfnyzDvWvIy95rDiwJvP29UwGb8SAP0KuhVA94QtuGpULRWsn7IF9A3UXa9-nbEXOW8BuAKlnrMz3rcg26ZbMHc52jCTI4MzxVBFV8WE3t9XA0XcI3kcvP1UhRhqnGikYCsKf2igOaZ84Dcp_qWA2VbXHvNEIf62odqYmfZYTPVhd735-JI9c-izfXV6l-zm68XP8-_11Y9vl-ebq9oo3sy14LhuHA6tk6AQlHWjU62SLbSOS4kNSMHXHI3sJRcDSLCdaHuJLSgxApdL9v6Ye5vi3c7mWU-UjfUeg427rNtyGSUb1RX57lEpOPSiK7uXTByhSTHnZJ2-TTRhutcc9KEHvdWHHvShBw2dLj2UoTen9N0w2fH_yOnwBbw9AcwGvUsYDOV_TpQwAXxd3Jejs-Vqe7JJZ0M2GDtSsmbWY6TH_vEARrGlRQ</recordid><startdate>20091001</startdate><enddate>20091001</enddate><creator>West, Christopher W.</creator><creator>Adler, Marc</creator><creator>Arnaiz, Danny</creator><creator>Chen, Deborah</creator><creator>Chu, Kieu</creator><creator>Gualtieri, Giovanna</creator><creator>Ho, Elena</creator><creator>Huwe, Christoph</creator><creator>Light, David</creator><creator>Phillips, Gary</creator><creator>Pulk, Rebecca</creator><creator>Sukovich, Drew</creator><creator>Whitlow, Marc</creator><creator>Yuan, Shendong</creator><creator>Bryant, Judi</creator><general>Elsevier Ltd</general><general>Elsevier</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20091001</creationdate><title>Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA)</title><author>West, Christopher W. ; Adler, Marc ; Arnaiz, Danny ; Chen, Deborah ; Chu, Kieu ; Gualtieri, Giovanna ; Ho, Elena ; Huwe, Christoph ; Light, David ; Phillips, Gary ; Pulk, Rebecca ; Sukovich, Drew ; Whitlow, Marc ; Yuan, Shendong ; Bryant, Judi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c416t-21a56fab7f304a04efdf4743707f133a6032151ac39312b030e82793a7042d013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Administration, Oral</topic><topic>Amidines - chemistry</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Animals</topic><topic>Benzylamines - chemistry</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Crystallography, X-Ray</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Humans</topic><topic>Hydrolases</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Serine protease</topic><topic>Serine Proteinase Inhibitors - administration & dosage</topic><topic>Serine Proteinase Inhibitors - chemical synthesis</topic><topic>Serine Proteinase Inhibitors - chemistry</topic><topic>Structure-Activity Relationship</topic><topic>uPA</topic><topic>Urokinase</topic><topic>Urokinase-Type Plasminogen Activator - antagonists & inhibitors</topic><topic>Urokinase-Type Plasminogen Activator - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>West, Christopher W.</creatorcontrib><creatorcontrib>Adler, Marc</creatorcontrib><creatorcontrib>Arnaiz, Danny</creatorcontrib><creatorcontrib>Chen, Deborah</creatorcontrib><creatorcontrib>Chu, Kieu</creatorcontrib><creatorcontrib>Gualtieri, Giovanna</creatorcontrib><creatorcontrib>Ho, Elena</creatorcontrib><creatorcontrib>Huwe, Christoph</creatorcontrib><creatorcontrib>Light, David</creatorcontrib><creatorcontrib>Phillips, Gary</creatorcontrib><creatorcontrib>Pulk, Rebecca</creatorcontrib><creatorcontrib>Sukovich, Drew</creatorcontrib><creatorcontrib>Whitlow, Marc</creatorcontrib><creatorcontrib>Yuan, Shendong</creatorcontrib><creatorcontrib>Bryant, Judi</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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>West, Christopher W.</au><au>Adler, Marc</au><au>Arnaiz, Danny</au><au>Chen, Deborah</au><au>Chu, Kieu</au><au>Gualtieri, Giovanna</au><au>Ho, Elena</au><au>Huwe, Christoph</au><au>Light, David</au><au>Phillips, Gary</au><au>Pulk, Rebecca</au><au>Sukovich, Drew</au><au>Whitlow, Marc</au><au>Yuan, Shendong</au><au>Bryant, Judi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA)</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2009-10-01</date><risdate>2009</risdate><volume>19</volume><issue>19</issue><spage>5712</spage><epage>5715</epage><pages>5712-5715</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The discovery, synthesis, and early SAR work on a benzyl amine containing series of uPA inhibitors is reported.
In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound
1, a significant change provided compounds in which the amidine, binding in the S1 pocket, was replaced with a primary amine. Further modifications led to the identification of potent, selective, and orally bioavailable uPA inhibitors.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19703768</pmid><doi>10.1016/j.bmcl.2009.08.008</doi><tpages>4</tpages></addata></record> |
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| subjects | Administration, Oral Amidines - chemistry Analytical, structural and metabolic biochemistry Animals Benzylamines - chemistry Binding Sites Biological and medical sciences Crystallography, X-Ray Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Humans Hydrolases Medical sciences Miscellaneous Pharmacology. Drug treatments Rats Serine protease Serine Proteinase Inhibitors - administration & dosage Serine Proteinase Inhibitors - chemical synthesis Serine Proteinase Inhibitors - chemistry Structure-Activity Relationship uPA Urokinase Urokinase-Type Plasminogen Activator - antagonists & inhibitors Urokinase-Type Plasminogen Activator - metabolism |
| title | Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA) |
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