Development of orally active nonpeptidic inhibitors of human neutrophil elastase

5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and m iscellaneous derivatives were synthesized and biologically evaluated on bot h in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an alpha -keto-1,3,4-oxadiazole moiety to bind covalent ly to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among t hose tested, compounds 11a-c,e,i-1(F), 11d,e,k(H), ald,e,k(F), and ald,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical eval uation based on its oral potency, duration of action, enzyme selectivity, s afety profile, and ease of synthesis. Structure-activity relationships (SAR s) are discussed.