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.