1-Methyl and 1-(2-hydroxyalkyl)-5-(3-alkyl/cycloalkyl/phenyl/naphthylureido)-1H-pyrazole-4-carboxylic acid ethyl esters as potent human neutrophil chemotaxis inhibitors
In this paper we report the synthesis and the chemotaxis inhibitory activity of a number of 1H-pyrazole-4-carboxylic acid ethyl esters 2 functionalized in N1 with a methyl group or different hydroxyalkyl chains and in position 5 with a series of 3-substituted urea groups. These compounds were design...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2009-05, Vol.17 (9), p.3379-3387 |
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| creator | Bruno, Olga Brullo, Chiara Bondavalli, Francesco Schenone, Silvia Spisani, Susanna Falzarano, Maria Sofia Varani, Katia Barocelli, Elisabetta Ballabeni, Vigilio Giorgio, Carmine Tognolini, Massimiliano |
| description | In this paper we report the synthesis and the chemotaxis inhibitory activity of a number of 1H-pyrazole-4-carboxylic acid ethyl esters 2 functionalized in N1 with a methyl group or different hydroxyalkyl chains and in position 5 with a series of 3-substituted urea groups. These compounds were designed as development of previous pyrazole-urea derivatives that resulted potent IL8-induced neutrophil chemotaxis inhibitors in vitro. Most of the new compounds revealed a potent inhibition of both IL8- and fMLP-OMe-stimulated neutrophil chemotaxis. The most active compounds in the fMLP-OMe induced chemotaxis test showed IC(50) in the range 0.19 nM-2 microM; but we observed a very strong inhibition in the IL8-induced chemotaxis test, having the most active compounds IC(50) at pM concentrations. In vivo compounds 2e and 2f, although to a lesser extent, at 50mg/kg os decreased granulocyte infiltration in zymosan-induced peritonitis in mice. |
| doi_str_mv | 10.1016/j.bmc.2009.03.035 |
| format | Article |
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In vivo compounds 2e and 2f, although to a lesser extent, at 50mg/kg os decreased granulocyte infiltration in zymosan-induced peritonitis in mice.</description><subject>Animals</subject><subject>Chemotaxis, Leukocyte - drug effects</subject><subject>Drug Design</subject><subject>Esters - chemical synthesis</subject><subject>Esters - chemistry</subject><subject>Esters - pharmacology</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Interleukin-8 - antagonists & inhibitors</subject><subject>Interleukin-8 - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>N-Formylmethionine Leucyl-Phenylalanine - analogs & derivatives</subject><subject>N-Formylmethionine Leucyl-Phenylalanine - antagonists & inhibitors</subject><subject>N-Formylmethionine Leucyl-Phenylalanine - pharmacology</subject><subject>Neutrophils - cytology</subject><subject>Neutrophils - drug effects</subject><subject>Protein Binding</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFUU1v1DAUtBAVXQo_gAvyCbUHb_0d-4gqSpGKeoGz5TiO4sWJg51IDb-In4m3uxLSk2YOM_Pe0wDwgeA9wUTeHvbt6PYUY73HrI54BXaES44Y0-Q12GEtFcJKy0vwtpQDxphyTd6AS6KZpFzJHfhL0He_DFuEduogQdcUDVuX0_Nm468t3iCBrhl64bduczGd6Dz4qcJk5-FoXrMPXbpB5AHNW7Z_UvSII2dzW4NicNC60MHTHl8Wnwu0Bc5p8dMCh3W0E5z8uuQ0DyFCN_gxLfY5FBimIbRhSbm8Axe9jcW_P-MV-Hn_5cfdA3p8-vrt7vMjcoyRBYnWSdVz3lOpK3BO-67-3XaKUdtoKzBVrReYNLIRSntGZGetxUoq6ptGsCvw6ZQ75_R7rceaMRTnY7STT2sxFAvJBGNVSE5Cl1Mp2fdmzmG0eTMEm2M95mBqPeZYj8GszjH84zl8bUff_Xec-2D_AOgpjlw</recordid><startdate>20090501</startdate><enddate>20090501</enddate><creator>Bruno, Olga</creator><creator>Brullo, Chiara</creator><creator>Bondavalli, Francesco</creator><creator>Schenone, Silvia</creator><creator>Spisani, Susanna</creator><creator>Falzarano, Maria Sofia</creator><creator>Varani, Katia</creator><creator>Barocelli, Elisabetta</creator><creator>Ballabeni, Vigilio</creator><creator>Giorgio, Carmine</creator><creator>Tognolini, Massimiliano</creator><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>7QR</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20090501</creationdate><title>1-Methyl and 1-(2-hydroxyalkyl)-5-(3-alkyl/cycloalkyl/phenyl/naphthylureido)-1H-pyrazole-4-carboxylic acid ethyl esters as potent human neutrophil chemotaxis inhibitors</title><author>Bruno, Olga ; Brullo, Chiara ; Bondavalli, Francesco ; Schenone, Silvia ; Spisani, Susanna ; Falzarano, Maria Sofia ; Varani, Katia ; Barocelli, Elisabetta ; Ballabeni, Vigilio ; Giorgio, Carmine ; Tognolini, Massimiliano</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c331t-5bc68f44f269f44442fd000bd832a79a5028be501767589e316daaa08682e7753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Chemotaxis, Leukocyte - drug effects</topic><topic>Drug Design</topic><topic>Esters - chemical synthesis</topic><topic>Esters - chemistry</topic><topic>Esters - pharmacology</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Interleukin-8 - antagonists & inhibitors</topic><topic>Interleukin-8 - pharmacology</topic><topic>Male</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>N-Formylmethionine Leucyl-Phenylalanine - analogs & derivatives</topic><topic>N-Formylmethionine Leucyl-Phenylalanine - antagonists & inhibitors</topic><topic>N-Formylmethionine Leucyl-Phenylalanine - pharmacology</topic><topic>Neutrophils - cytology</topic><topic>Neutrophils - drug effects</topic><topic>Protein Binding</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bruno, Olga</creatorcontrib><creatorcontrib>Brullo, Chiara</creatorcontrib><creatorcontrib>Bondavalli, Francesco</creatorcontrib><creatorcontrib>Schenone, Silvia</creatorcontrib><creatorcontrib>Spisani, Susanna</creatorcontrib><creatorcontrib>Falzarano, Maria Sofia</creatorcontrib><creatorcontrib>Varani, Katia</creatorcontrib><creatorcontrib>Barocelli, Elisabetta</creatorcontrib><creatorcontrib>Ballabeni, Vigilio</creatorcontrib><creatorcontrib>Giorgio, Carmine</creatorcontrib><creatorcontrib>Tognolini, Massimiliano</creatorcontrib><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>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bruno, Olga</au><au>Brullo, Chiara</au><au>Bondavalli, Francesco</au><au>Schenone, Silvia</au><au>Spisani, Susanna</au><au>Falzarano, Maria Sofia</au><au>Varani, Katia</au><au>Barocelli, Elisabetta</au><au>Ballabeni, Vigilio</au><au>Giorgio, Carmine</au><au>Tognolini, Massimiliano</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>1-Methyl and 1-(2-hydroxyalkyl)-5-(3-alkyl/cycloalkyl/phenyl/naphthylureido)-1H-pyrazole-4-carboxylic acid ethyl esters as potent human neutrophil chemotaxis inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2009-05-01</date><risdate>2009</risdate><volume>17</volume><issue>9</issue><spage>3379</spage><epage>3387</epage><pages>3379-3387</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>In this paper we report the synthesis and the chemotaxis inhibitory activity of a number of 1H-pyrazole-4-carboxylic acid ethyl esters 2 functionalized in N1 with a methyl group or different hydroxyalkyl chains and in position 5 with a series of 3-substituted urea groups. 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| ispartof | Bioorganic & medicinal chemistry, 2009-05, Vol.17 (9), p.3379-3387 |
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| subjects | Animals Chemotaxis, Leukocyte - drug effects Drug Design Esters - chemical synthesis Esters - chemistry Esters - pharmacology Humans Inhibitory Concentration 50 Interleukin-8 - antagonists & inhibitors Interleukin-8 - pharmacology Male Mice Molecular Structure N-Formylmethionine Leucyl-Phenylalanine - analogs & derivatives N-Formylmethionine Leucyl-Phenylalanine - antagonists & inhibitors N-Formylmethionine Leucyl-Phenylalanine - pharmacology Neutrophils - cytology Neutrophils - drug effects Protein Binding Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Structure-Activity Relationship |
| title | 1-Methyl and 1-(2-hydroxyalkyl)-5-(3-alkyl/cycloalkyl/phenyl/naphthylureido)-1H-pyrazole-4-carboxylic acid ethyl esters as potent human neutrophil chemotaxis inhibitors |
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