1eau: Difference between revisions
New page: left|200px<br /><applet load="1eau" size="450" color="white" frame="true" align="right" spinBox="true" caption="1eau, resolution 2.0Å" /> '''NONPEPTIDIC INHIBITOR... |
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[[Image:1eau.jpg|left|200px]]<br /><applet load="1eau" size=" | [[Image:1eau.jpg|left|200px]]<br /><applet load="1eau" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1eau, resolution 2.0Å" /> | caption="1eau, resolution 2.0Å" /> | ||
'''NONPEPTIDIC INHIBITORS OF HUMAN LEUKOCYTE ELASTASE. 6. DESIGN OF A POTENT, INTRATRACHEALLY ACTIVE, PYRIDONE-BASED TRIFLUOROMETHYL KETONE'''<br /> | '''NONPEPTIDIC INHIBITORS OF HUMAN LEUKOCYTE ELASTASE. 6. DESIGN OF A POTENT, INTRATRACHEALLY ACTIVE, PYRIDONE-BASED TRIFLUOROMETHYL KETONE'''<br /> | ||
==Overview== | ==Overview== | ||
Further modification of the 3-amino substituent in a trifluoromethyl | Further modification of the 3-amino substituent in a trifluoromethyl ketone-based series of 3-amino-6-phenylpyridin-2-ones that had been optimized for oral activity led to analogs that were potent intratracheal inhibitors in a model of HLE-induced lung damage in the hamster. The best 3-amino substituent for intratracheal activity is [4-[N-[(4-chlorophenyl)sulfonyl]-carbamoyl]phenyl]sulfonyl. At a 30 min prechallenge interval, compound 9, which incorporates this substituent, had an ED50 of approximately 2 nmol/animal and, qualitatively, afforded a very similar dose-response relationship to that found with a peptidic trifluoromethyl ketone inhibitor, ICI 200,355. | ||
==About this Structure== | ==About this Structure== | ||
1EAU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with NA, SO4 and BDK as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Pancreatic_elastase Pancreatic elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.36 3.4.21.36] Full crystallographic information is available from [http:// | 1EAU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with <scene name='pdbligand=NA:'>NA</scene>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=BDK:'>BDK</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Pancreatic_elastase Pancreatic elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.36 3.4.21.36] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EAU OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: hydrolase (serine protease)]] | [[Category: hydrolase (serine protease)]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:25:48 2008'' | ||
Revision as of 10:25, 21 February 2008
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NONPEPTIDIC INHIBITORS OF HUMAN LEUKOCYTE ELASTASE. 6. DESIGN OF A POTENT, INTRATRACHEALLY ACTIVE, PYRIDONE-BASED TRIFLUOROMETHYL KETONE
Overview
Further modification of the 3-amino substituent in a trifluoromethyl ketone-based series of 3-amino-6-phenylpyridin-2-ones that had been optimized for oral activity led to analogs that were potent intratracheal inhibitors in a model of HLE-induced lung damage in the hamster. The best 3-amino substituent for intratracheal activity is [4-[N-[(4-chlorophenyl)sulfonyl]-carbamoyl]phenyl]sulfonyl. At a 30 min prechallenge interval, compound 9, which incorporates this substituent, had an ED50 of approximately 2 nmol/animal and, qualitatively, afforded a very similar dose-response relationship to that found with a peptidic trifluoromethyl ketone inhibitor, ICI 200,355.
About this Structure
1EAU is a Single protein structure of sequence from Sus scrofa with NA, SO4 and BDK as ligands. Active as Pancreatic elastase, with EC number 3.4.21.36 Full crystallographic information is available from OCA.
Reference
Nonpeptidic inhibitors of human leukocyte elastase. 6. Design of a potent, intratracheally active, pyridone-based trifluoromethyl ketone., Bernstein PR, Gomes BC, Kosmider BJ, Vacek EP, Williams JC, J Med Chem. 1995 Jan 6;38(1):212-5. PMID:7837235
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