title: Discovery and biological activity of orally active peptidyl trifluoromethyl ketone inhibitors of human neutrophil elastase.
abstract: Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protection against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 micrograms/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.
authors.affiliation: Department of Medicinal Chemistry, ZENECA Pharmaceuticals, A Business Unit of ZENECA Inc., Wilmington, Delaware 19850-5437, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Edwards
authors.forename: D W
authors.initials: DW
authors.lastname: Andisik
authors.forename: C A
authors.initials: CA
authors.lastname: Bryant
authors.forename: B
authors.initials: B
authors.lastname: Ewing
authors.forename: B
authors.initials: B
authors.lastname: Gomes
authors.forename: J J
authors.initials: JJ
authors.lastname: Lewis
authors.forename: D
authors.initials: D
authors.lastname: Rakiewicz
authors.forename: G
authors.initials: G
authors.lastname: Steelman
authors.forename: A
authors.initials: A
authors.lastname: Strimpler
authors.forename: D A
authors.initials: DA
authors.lastname: Trainor
authors.forename: P A
authors.initials: PA
authors.lastname: Tuthill
authors.forename: R C
authors.initials: RC
authors.lastname: Mauger
authors.forename: C A
authors.initials: CA
authors.lastname: Veale
authors.forename: R A
authors.initials: RA
authors.lastname: Wildonger
authors.forename: J C
authors.initials: JC
authors.lastname: Williams
authors.forename: D J
authors.initials: DJ
authors.lastname: Wolanin
authors.forename: M
authors.initials: M
authors.lastname: Zottola
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D006224:Cricetinae; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D004906:Erythrocyte Count; D006470:Hemorrhage / Q000517:prevention & control; D006801:Humans; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008168:Lung / Q000033:anatomy & histology; D008171:Lung Diseases / Q000517:prevention & control; D008297:Male; D008647:Mesocricetus; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; C106595:((4-methoxyphenyl)carbonyl)-valyl-N-(3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl))prolinamide; D019272:Leukocyte Elastase