1eat: Difference between revisions

Revision as of 13:25, 21 February 2008

NONPEPTIDIC INHIBITORS OF HUMAN LEUKOCYTE ELASTASE. 5. DESIGN, SYNTHESIS, AND X-RAY CRYSTALLOGRAPHY OF A SERIES OF ORALLY ACTIVE 5-AMINO-PYRIMIDIN-6-ONE-CONTAINING TRIFLUOROMETHYLKETONES

OverviewOverview

The effects of changes in substitution in a series of 5-amino-2-pyrimidin-6-ones on both in vitro activity and oral activity in an acute hemorrhagic assay have been explored. These compounds contained either a trifluoromethyl ketone or a boronic acid moiety to bind covalently to the Ser-195 hydroxyl of human leukocyte elastase (HLE). Boronic acid-containing inhibitors were found to be more potent than the corresponding trifluoromethyl ketones in vitro but were less active upon oral administration. Compound 13b was found to offer the best combination of oral potency, duration of action, and enzyme selectivity and, as such, was selected for further biological testing. X-ray crystallography of a cocrystallized complex of compound 19m and porcine pancreatic elastase demonstrated that the inhibitor is bound to the enzyme in a manner similar to that found previously for a closely related series of pyridone-containing inhibitors of HLE.

About this StructureAbout this Structure

1EAT is a Single protein structure of sequence from Sus scrofa with , and as ligands. Active as Pancreatic elastase, with EC number 3.4.21.36 Full crystallographic information is available from OCA.

ReferenceReference

Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, synthesis, and X-ray crystallography of a series of orally active 5-aminopyrimidin-6-one-containing trifluoromethyl ketones., Veale CA, Bernstein PR, Bryant C, Ceccarelli C, Damewood JR Jr, Earley R, Feeney SW, Gomes B, Kosmider BJ, Steelman GB, et al., J Med Chem. 1995 Jan 6;38(1):98-108. PMID:7837246

Page seeded by OCA on Thu Feb 21 12:25:46 2008

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OCA

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-[[Image:1eat.gif|left|200px]]<br /><applet load="1eat" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1eat.gif|left|200px]]<br /><applet load="1eat" size="350" color="white" frame="true" align="right" spinBox="true"
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 '''NONPEPTIDIC INHIBITORS OF HUMAN LEUKOCYTE ELASTASE. 5. DESIGN, SYNTHESIS, AND X-RAY CRYSTALLOGRAPHY OF A SERIES OF ORALLY ACTIVE 5-AMINO-PYRIMIDIN-6-ONE-CONTAINING TRIFLUOROMETHYLKETONES'''<br />
 ==Overview==
-The effects of changes in substitution in a series of, 5-amino-2-pyrimidin-6-ones on both in vitro activity and oral activity in, an acute hemorrhagic assay have been explored. These compounds contained, either a trifluoromethyl ketone or a boronic acid moiety to bind, covalently to the Ser-195 hydroxyl of human leukocyte elastase (HLE)., Boronic acid-containing inhibitors were found to be more potent than the, corresponding trifluoromethyl ketones in vitro but were less active upon, oral administration. Compound 13b was found to offer the best combination, of oral potency, duration of action, and enzyme selectivity and, as such, was selected for further biological testing. X-ray crystallography of a, cocrystallized complex of compound 19m and porcine pancreatic elastase, demonstrated that the inhibitor is bound to the enzyme in a manner similar, to that found previously for a closely related series of, pyridone-containing inhibitors of HLE.
+The effects of changes in substitution in a series of 5-amino-2-pyrimidin-6-ones on both in vitro activity and oral activity in an acute hemorrhagic assay have been explored. These compounds contained either a trifluoromethyl ketone or a boronic acid moiety to bind covalently to the Ser-195 hydroxyl of human leukocyte elastase (HLE). Boronic acid-containing inhibitors were found to be more potent than the corresponding trifluoromethyl ketones in vitro but were less active upon oral administration. Compound 13b was found to offer the best combination of oral potency, duration of action, and enzyme selectivity and, as such, was selected for further biological testing. X-ray crystallography of a cocrystallized complex of compound 19m and porcine pancreatic elastase demonstrated that the inhibitor is bound to the enzyme in a manner similar to that found previously for a closely related series of pyridone-containing inhibitors of HLE.
 ==About this Structure==
-EAT 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 TFI 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EAT OCA].
+EAT 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=TFI:'>TFI</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=1EAT OCA].
 ==Reference==
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 [[Category: hydrolase (serine protease)]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 13:51:59 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:25:46 2008''