1eat
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(New page: 200px<br /><applet load="1eat" size="450" color="white" frame="true" align="right" spinBox="true" caption="1eat, resolution 2.0Å" /> '''NONPEPTIDIC INHIBITOR...)
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Revision as of 11:44, 20 November 2007
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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
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.
About this Structure
1EAT is a Single protein structure of sequence from Sus scrofa with NA, SO4 and TFI 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. 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
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