title: Intracellular inhibition of human neutrophil elastase by orally active pyrrolidine-trans-lactams.
abstract: Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.
authors.affiliation: Medical Chemistry 2, Glaxo Wellcome Medicines Research Centre, Stevenage, UK. sjfm5947@glaxowellcome.co.uk
authors.forename: S J
authors.initials: SJ
authors.lastname: Macdonald
authors.forename: M D
authors.initials: MD
authors.lastname: Dowle
authors.forename: L A
authors.initials: LA
authors.lastname: Harrison
authors.forename: J E
authors.initials: JE
authors.lastname: Spooner
authors.forename: P
authors.initials: P
authors.lastname: Shah
authors.forename: M R
authors.initials: MR
authors.lastname: Johnson
authors.forename: G G
authors.initials: GG
authors.lastname: Inglis
authors.forename: G D
authors.initials: GD
authors.lastname: Clarke
authors.forename: D J
authors.initials: DJ
authors.lastname: Belton
authors.forename: R A
authors.initials: RA
authors.lastname: Smith
authors.forename: C R
authors.initials: CR
authors.lastname: Molloy
authors.forename: M
authors.initials: M
authors.lastname: Dixon
authors.forename: G
authors.initials: G
authors.lastname: Murkitt
authors.forename: R E
authors.initials: RE
authors.lastname: Godward
authors.forename: T
authors.initials: T
authors.lastname: Skarzynski
authors.forename: O M
authors.initials: OM
authors.lastname: Singh
authors.forename: K A
authors.initials: KA
authors.lastname: Kumar
authors.forename: S T
authors.initials: ST
authors.lastname: Hodgson
authors.forename: E
authors.initials: E
authors.lastname: McDonald
authors.forename: G W
authors.initials: GW
authors.lastname: Hardy
authors.forename: H
authors.initials: H
authors.lastname: Finch
authors.forename: D C
authors.initials: DC
authors.lastname: Humphreys
authors.forename: G
authors.initials: G
authors.lastname: Fleetwood
mesh_terms: D000215:Acylation; D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010179:Pancreas / Q000201:enzymology; D011485:Protein Binding; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D007769:Lactams; D011759:Pyrrolidines; D019272:Leukocyte Elastase