1eas | pdb_00001eas

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

spinqualitylabelsall models 1eas, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1eas is a 1 chain structure with sequence from Pig. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NA, SO4, TFK Activity: Pancreatic elastase, with EC number 3.4.21.36 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CELA1_PIG] Acts upon elastin. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Elastase 3D structures

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