title: Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase.
abstract: This paper describes the development a series of peptidyl trifluoromethyl ketone inhibitors of human leukocyte elastase which are found to have excellent pharmacological profiles. Methods have been developed that allow for the synthesis of these inhibitors in stereochemically pure form. Two of these compounds, 1k and 1l, have high levels of oral bioavailability in several species. Compound 1l has entered development as ZD8321 and is presently undergoing clinical evaluation. These compounds demonstrate that peptidyl trifluoromethyl ketone inhibitors can achieve high levels of oral activity and bioavailability, and therefore they may prove useful as therapeutic agents in the treatment of diseases in which elastase is implicated.
authors.affiliation: Department of Medicinal Chemistry, ZENECA Pharmaceuticals, A Business Unit of ZENECA Inc., Wilmington, Delaware 19897, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Veale
authors.forename: P R
authors.initials: PR
authors.lastname: Bernstein
authors.forename: C M
authors.initials: CM
authors.lastname: Bohnert
authors.forename: F J
authors.initials: FJ
authors.lastname: Brown
authors.forename: C
authors.initials: C
authors.lastname: Bryant
authors.forename: J R
authors.initials: JR
authors.lastname: Damewood
authors.forename: R
authors.initials: R
authors.lastname: Earley
authors.forename: S W
authors.initials: SW
authors.lastname: Feeney
authors.forename: P D
authors.initials: PD
authors.lastname: Edwards
authors.forename: B
authors.initials: B
authors.lastname: Gomes
authors.forename: J M
authors.initials: JM
authors.lastname: Hulsizer
authors.forename: B J
authors.initials: BJ
authors.lastname: Kosmider
authors.forename: R D
authors.initials: RD
authors.lastname: Krell
authors.forename: G
authors.initials: G
authors.lastname: Moore
authors.forename: T W
authors.initials: TW
authors.lastname: Salcedo
authors.forename: A
authors.initials: A
authors.lastname: Shaw
authors.forename: D S
authors.initials: DS
authors.lastname: Silberstein
authors.forename: G B
authors.initials: GB
authors.lastname: Steelman
authors.forename: M
authors.initials: M
authors.lastname: Stein
authors.forename: A
authors.initials: A
authors.lastname: Strimpler
authors.forename: R M
authors.initials: RM
authors.lastname: Thomas
authors.forename: E P
authors.initials: EP
authors.lastname: Vacek
authors.forename: J C
authors.initials: JC
authors.lastname: Williams
authors.forename: D J
authors.initials: DJ
authors.lastname: Wolanin
authors.forename: S
authors.initials: S
authors.lastname: Woolson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006224:Cricetinae; D004285:Dogs; D006801:Humans; D007536:Isomerism; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; C069366:ICI 200355; D019272:Leukocyte Elastase; C108686:ZD 8321