Inhibition of Human Neutrophil Elastase with Peptidyl Electrophilic Ketones. 2. Orally Active PG-Val-Pro-Val Pentafluoroethyl Ketones
Valylprolyvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neutrophil elastase (HNE). Several of these compounds were found to be orally active in HNE-induced rat and hamster lung hemorrhage models. The compound with 4-(4-mo...
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| Veröffentlicht in: | Journal of medicinal chemistry 1994-12, Vol.37 (26), p.4538-4553 |
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| container_end_page | 4553 |
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| container_issue | 26 |
| container_start_page | 4538 |
| container_title | Journal of medicinal chemistry |
| container_volume | 37 |
| creator | Angelastro, Michael R Baugh, Larry E Bey, Philippe Burkhart, Joseph P Chen, Teng-Man Durham, Sherrie L Hare, C. Michelle Huber, Edward W Janusz, Michael J |
| description | Valylprolyvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neutrophil elastase (HNE). Several of these compounds were found to be orally active in HNE-induced rat and hamster lung hemorrhage models. The compound with 4-(4-morpholinylcarbonyl)benzoyl as the protecting group, 71 (MDL 101,146), was studied in greater detail. Hydration and epimerization studies were performed on 71 and related compounds in various media, including human blood serum. High-performance liquid chromatography studies on a reversed-phase system as a measure of the lipophilicity of 71 and related compounds revealed a small range of relative retention times wherein the orally active compounds fell. The Ki value determined for 71 vs HNE was 25 nM. |
| doi_str_mv | 10.1021/jm00052a013 |
| format | Article |
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Orally Active PG-Val-Pro-Val Pentafluoroethyl Ketones</title><source>ACS Publications</source><source>MEDLINE</source><creator>Angelastro, Michael R ; Baugh, Larry E ; Bey, Philippe ; Burkhart, Joseph P ; Chen, Teng-Man ; Durham, Sherrie L ; Hare, C. Michelle ; Huber, Edward W ; Janusz, Michael J</creator><creatorcontrib>Angelastro, Michael R ; Baugh, Larry E ; Bey, Philippe ; Burkhart, Joseph P ; Chen, Teng-Man ; Durham, Sherrie L ; Hare, C. Michelle ; Huber, Edward W ; Janusz, Michael J</creatorcontrib><description>Valylprolyvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neutrophil elastase (HNE). Several of these compounds were found to be orally active in HNE-induced rat and hamster lung hemorrhage models. The compound with 4-(4-morpholinylcarbonyl)benzoyl as the protecting group, 71 (MDL 101,146), was studied in greater detail. Hydration and epimerization studies were performed on 71 and related compounds in various media, including human blood serum. High-performance liquid chromatography studies on a reversed-phase system as a measure of the lipophilicity of 71 and related compounds revealed a small range of relative retention times wherein the orally active compounds fell. 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Michelle</creatorcontrib><creatorcontrib>Huber, Edward W</creatorcontrib><creatorcontrib>Janusz, Michael J</creatorcontrib><title>Inhibition of Human Neutrophil Elastase with Peptidyl Electrophilic Ketones. 2. Orally Active PG-Val-Pro-Val Pentafluoroethyl Ketones</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Valylprolyvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neutrophil elastase (HNE). Several of these compounds were found to be orally active in HNE-induced rat and hamster lung hemorrhage models. The compound with 4-(4-morpholinylcarbonyl)benzoyl as the protecting group, 71 (MDL 101,146), was studied in greater detail. Hydration and epimerization studies were performed on 71 and related compounds in various media, including human blood serum. High-performance liquid chromatography studies on a reversed-phase system as a measure of the lipophilicity of 71 and related compounds revealed a small range of relative retention times wherein the orally active compounds fell. The Ki value determined for 71 vs HNE was 25 nM.</description><subject>Administration, Oral</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Cricetinae</subject><subject>Hemorrhage - drug therapy</subject><subject>Humans</subject><subject>Ketones - analysis</subject><subject>Ketones - chemical synthesis</subject><subject>Ketones - pharmacology</subject><subject>Leukocyte Elastase</subject><subject>Molecular Sequence Data</subject><subject>Pancreatic Elastase - antagonists & inhibitors</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE9v1DAUxC0EKkvhxBnJJzigbB3bieNjqUr_ULWLusDRcrzPWi9OvNgOsB-A792sNqp64DTSm9_MkwahtyWZl4SWJ5uOEFJRTUr2DM3KipKCN4Q_RzNCKC1oTdlL9CqlzYixkrIjdCSElJzwGfp31a9d67ILPQ4WXw6d7vEtDDmG7dp5fO51yjoB_uPyGi9gm91qtz-DmRBn8BfIoYc0x3SO76L2fodPTXa_AS8uiu_aF4sY9jrm-6ytH0IMkNdjz5R8jV5Y7RO8mfQYfft8vjy7LG7uLq7OTm8KTWuZi4bL0nAtqspqDcYAtNC0jeSmIbqujG6qpuVGGpArC5wLwexKMGlsDdQyyY7R-0PvNoZfA6SsOpcMeK97CENSom6kZBUdwY8H0MSQUgSrttF1Ou5USdR-dPVk9JF-N9UObQerR3ZaefSLg-9Shr-Pto4_VS2YqNRyca-W99c_qPj6Sd2O_IcDr01SmzDEfhzlv58fAHEemn8</recordid><startdate>19941201</startdate><enddate>19941201</enddate><creator>Angelastro, Michael R</creator><creator>Baugh, Larry E</creator><creator>Bey, Philippe</creator><creator>Burkhart, Joseph P</creator><creator>Chen, Teng-Man</creator><creator>Durham, Sherrie L</creator><creator>Hare, C. 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Orally Active PG-Val-Pro-Val Pentafluoroethyl Ketones</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1994-12-01</date><risdate>1994</risdate><volume>37</volume><issue>26</issue><spage>4538</spage><epage>4553</epage><pages>4538-4553</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Valylprolyvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neutrophil elastase (HNE). Several of these compounds were found to be orally active in HNE-induced rat and hamster lung hemorrhage models. The compound with 4-(4-morpholinylcarbonyl)benzoyl as the protecting group, 71 (MDL 101,146), was studied in greater detail. Hydration and epimerization studies were performed on 71 and related compounds in various media, including human blood serum. High-performance liquid chromatography studies on a reversed-phase system as a measure of the lipophilicity of 71 and related compounds revealed a small range of relative retention times wherein the orally active compounds fell. The Ki value determined for 71 vs HNE was 25 nM.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>7799404</pmid><doi>10.1021/jm00052a013</doi><tpages>16</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1994-12, Vol.37 (26), p.4538-4553 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | ACS Publications; MEDLINE |
| subjects | Administration, Oral Amino Acid Sequence Animals Chromatography, High Pressure Liquid Cricetinae Hemorrhage - drug therapy Humans Ketones - analysis Ketones - chemical synthesis Ketones - pharmacology Leukocyte Elastase Molecular Sequence Data Pancreatic Elastase - antagonists & inhibitors Rats Structure-Activity Relationship |
| title | Inhibition of Human Neutrophil Elastase with Peptidyl Electrophilic Ketones. 2. Orally Active PG-Val-Pro-Val Pentafluoroethyl Ketones |
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