N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists
Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series ha...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-09, Vol.21 (18), p.5283-5288 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Muraglia, Ester Ontoria, Jesus M. Branca, Danila Dessole, Gabriella Bresciani, Alberto Fonsi, Massimiliano Giuliano, Claudio Llauger Bufi, Laura Monteagudo, Edith Palumbi, Maria Cecilia Torrisi, Caterina Rowley, Michael Steinkühler, Christian Jones, Philip |
| description | Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies. |
| doi_str_mv | 10.1016/j.bmcl.2011.07.030 |
| format | Article |
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A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies.</description><subject>Amides - chemical synthesis</subject><subject>Amides - chemistry</subject><subject>Amides - pharmacology</subject><subject>antagonists</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>blood serum</subject><subject>General aspects</subject><subject>Hedgehog inhibitor</subject><subject>Hedgehog pathway</subject><subject>in vivo studies</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - chemical synthesis</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - pharmacology</subject><subject>rats</subject><subject>Receptors, G-Protein-Coupled - antagonists & inhibitors</subject><subject>signal transduction</subject><subject>Smoothened antagonist</subject><subject>Smoothened Receptor</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>urea</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>eNp9kU1v1DAQhi0EokvhD3CAXBBFqsPYcRJH4oIqvqQKDlCJmzVx7F0vTpzaWcT21-PVLnDjNIf3mQ89Q8hTBiUD1rzelv2ofcmBsRLaEiq4R1ZMNIJWAur7ZAVdA1R24vsZeZTSFoAJEOIhOeNMAu9EtSLhM73gFP2PvcfRTcEsm71_RQW9YJf8UtDwCweHd8HTmuZgdrOJeOcmQxnVGPucj24wqcBUbNx64_fFHBYzLUUaQ1g2ZjJDgdOC6zC5tKTH5IFFn8yTUz0nN-_ffbv6SK-_fPh09faaagHdQrlsASsuEaqWW7S27hrGOyZla7WRohpsw1gra-hQWDsMvbR9x6zsdN1WHKtz8vI4d47hdmfSokaXtPEeJxN2SUkppOhA1pnkR1LHkFI0Vs3RjRj3ioE6eFZbdfCsDp4VtCp7zk3PTuN3_WiGvy1_xGbgxQnApNHbiJN26R8naqglP2x_fuQsBoXrmJmbr3lTnZ9V1Vy0mXhzJEzW9dOZqJJ2ZtJmcNHoRQ3B_e_S37yQo-4</recordid><startdate>20110915</startdate><enddate>20110915</enddate><creator>Muraglia, Ester</creator><creator>Ontoria, Jesus M.</creator><creator>Branca, Danila</creator><creator>Dessole, Gabriella</creator><creator>Bresciani, Alberto</creator><creator>Fonsi, Massimiliano</creator><creator>Giuliano, Claudio</creator><creator>Llauger Bufi, Laura</creator><creator>Monteagudo, Edith</creator><creator>Palumbi, Maria Cecilia</creator><creator>Torrisi, Caterina</creator><creator>Rowley, Michael</creator><creator>Steinkühler, Christian</creator><creator>Jones, Philip</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></search><sort><creationdate>20110915</creationdate><title>N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists</title><author>Muraglia, Ester ; Ontoria, Jesus M. ; Branca, Danila ; Dessole, Gabriella ; Bresciani, Alberto ; Fonsi, Massimiliano ; Giuliano, Claudio ; Llauger Bufi, Laura ; Monteagudo, Edith ; Palumbi, Maria Cecilia ; Torrisi, Caterina ; Rowley, Michael ; Steinkühler, Christian ; Jones, Philip</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c409t-2870a328a0372faff5961291887fce843df61178509a4ffddb8fb91f89c5732a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Amides - chemical synthesis</topic><topic>Amides - chemistry</topic><topic>Amides - pharmacology</topic><topic>antagonists</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>blood serum</topic><topic>General aspects</topic><topic>Hedgehog inhibitor</topic><topic>Hedgehog pathway</topic><topic>in vivo studies</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperazines - chemical synthesis</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - pharmacology</topic><topic>rats</topic><topic>Receptors, G-Protein-Coupled - antagonists & inhibitors</topic><topic>signal transduction</topic><topic>Smoothened antagonist</topic><topic>Smoothened Receptor</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>urea</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Muraglia, Ester</creatorcontrib><creatorcontrib>Ontoria, Jesus M.</creatorcontrib><creatorcontrib>Branca, Danila</creatorcontrib><creatorcontrib>Dessole, Gabriella</creatorcontrib><creatorcontrib>Bresciani, Alberto</creatorcontrib><creatorcontrib>Fonsi, Massimiliano</creatorcontrib><creatorcontrib>Giuliano, Claudio</creatorcontrib><creatorcontrib>Llauger Bufi, Laura</creatorcontrib><creatorcontrib>Monteagudo, Edith</creatorcontrib><creatorcontrib>Palumbi, Maria Cecilia</creatorcontrib><creatorcontrib>Torrisi, Caterina</creatorcontrib><creatorcontrib>Rowley, Michael</creatorcontrib><creatorcontrib>Steinkühler, Christian</creatorcontrib><creatorcontrib>Jones, Philip</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><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Muraglia, Ester</au><au>Ontoria, Jesus M.</au><au>Branca, Danila</au><au>Dessole, Gabriella</au><au>Bresciani, Alberto</au><au>Fonsi, Massimiliano</au><au>Giuliano, Claudio</au><au>Llauger Bufi, Laura</au><au>Monteagudo, Edith</au><au>Palumbi, Maria Cecilia</au><au>Torrisi, Caterina</au><au>Rowley, Michael</au><au>Steinkühler, Christian</au><au>Jones, Philip</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-09-15</date><risdate>2011</risdate><volume>21</volume><issue>18</issue><spage>5283</spage><epage>5288</epage><pages>5283-5288</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. 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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2011-09, Vol.21 (18), p.5283-5288 |
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| language | eng |
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| subjects | Amides - chemical synthesis Amides - chemistry Amides - pharmacology antagonists Antineoplastic agents Biological and medical sciences blood serum General aspects Hedgehog inhibitor Hedgehog pathway in vivo studies Medical sciences Molecular Structure Pharmacology. Drug treatments Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacology rats Receptors, G-Protein-Coupled - antagonists & inhibitors signal transduction Smoothened antagonist Smoothened Receptor Stereoisomerism Structure-Activity Relationship urea |
| title | N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists |
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