title: Inhibition of human neutrophil elastase. 4. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of P2-modified, orally active peptidyl pentafluoroethyl ketones.
abstract: A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.
authors.affiliation: Hoechst Marion Roussel Inc., 2110 East Galbraith Road, Cincinnati, Ohio 45215, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Cregge
authors.forename: S L
authors.initials: SL
authors.lastname: Durham
authors.forename: R A
authors.initials: RA
authors.lastname: Farr
authors.forename: S L
authors.initials: SL
authors.lastname: Gallion
authors.forename: C M
authors.initials: CM
authors.lastname: Hare
authors.forename: R V
authors.initials: RV
authors.lastname: Hoffman
authors.forename: M J
authors.initials: MJ
authors.lastname: Janusz
authors.forename: H O
authors.initials: HO
authors.lastname: Kim
authors.forename: J R
authors.initials: JR
authors.lastname: Koehl
authors.forename: S
authors.initials: S
authors.lastname: Mehdi
authors.forename: W A
authors.initials: WA
authors.lastname: Metz
authors.forename: N P
authors.initials: NP
authors.lastname: Peet
authors.forename: J T
authors.initials: JT
authors.lastname: Pelton
authors.forename: H A
authors.initials: HA
authors.lastname: Schreuder
authors.forename: S
authors.initials: S
authors.lastname: Sunder
authors.forename: C
authors.initials: C
authors.lastname: Tardif
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000737:chemistry; D001665:Binding Sites; D006224:Cricetinae; D018360:Crystallography, X-Ray; D015195:Drug Design; D005466:Fluorocarbons / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006470:Hemorrhage / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D008958:Models, Molecular; D008968:Molecular Conformation; D009504:Neutrophils / Q000201:enzymology*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D001384:Azetidines; D005466:Fluorocarbons; D007546:Isoquinolines; D007659:Ketones; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; C082735:azetidine; D011392:Proline; C010983:homoproline; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; C039109:isoquinoline