1eas
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(New page: 200px<br /><applet load="1eas" size="450" color="white" frame="true" align="right" spinBox="true" caption="1eas, resolution 1.8Å" /> '''NONPEPTIDIC INHIBITOR...)
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Revision as of 11:44, 20 November 2007
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NONPEPTIDIC INHIBITORS OF HUMAN LEUKOCYTE ELASTASE. 3. DESIGN, SYNTHESIS, X-RAY CRYSTALLOGRAPHIC ANALYSIS, AND STRUCTURE-ACTIVITY RELATIONSHIPS FOR A SERIES OF ORALLY ACTIVE 3-AMINO-6-PHENYLPYRIDIN-2-ONE TRIFLUOROMETHYL KETONES
Overview
A series of nonpeptidic inhibitors of human leukocyte elastase (HLE) is, reported. These trifluoromethyl ketone-based inhibitors contain a, 3-amino-6-phenylpyridone group as a central template. The effect of, varying the N-3 substituent in these inhibitors on in vitro potency, physical properties, and oral activity in a hamster based, HLE-induced, lung damage model is described. The variety of substituents at this, position that have little effect on in vitro potency supports the idea, that this region of the molecule does not interact strongly with the, enzyme. One exception to this generality is 13k, which is substituted with, a (4-acetamidophenyl)sulfonyl group. This compound has a K(i) of 0.7 nM, and is, in vitro, the most potent inhibitor in the series. In contrast, variation of the N-3 substituent was found to have a dramatic effect on, activity after oral administration. Several analogs, including the parent, amine, 7, formamide, 2u, benzyl sulfamide, 13e, and benzyl sulfonamide, 13f, show significant activity when administered at an oral dose of 2.5, mg/kg. Support for the modeling-based design concepts was obtained through, in vitro SAR results and X-ray crystallographic analysis of the complex, between 13d and porcine pancreatic elastase (PPE), a closely related, enzyme.
About this Structure
1EAS is a Single protein structure of sequence from Sus scrofa with NA, SO4 and TFK 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. 3. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of orally active 3-amino-6-phenylpyridin-2-one trifluoromethyl ketones., Bernstein PR, Andisik D, Bradley PK, Bryant CB, Ceccarelli C, Damewood JR Jr, Earley R, Edwards PD, Feeney S, Gomes BC, et al., J Med Chem. 1994 Sep 30;37(20):3313-26. PMID:7932559
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