title: Orally active beta-lactam inhibitors of human leukocyte elastase-1. Activity of 3,3-diethyl-2-azetidinones.
abstract: A thorough analysis of the mechanism of inhibition of human leukocyte elastase (HLE) by a monocyclic beta-lactam and the mechanism of beta-lactam hydrolysis led to the preparation of potent and highly stable inhibitors of HLE. This work led to the identification of 4-[(4-carboxyphenyl)-oxy]-3,3-diethyl-1- [[(phenylmethyl)amino]carbonyl]-2-azetidinone (2) as the first orally active inhibitor of human leukocyte elastase (HLE). Analogs of 2 with different substituents on the urea N were synthesized and evaluated for their activity in vitro against HLE as well as in vivo in a hamster lung hemorrhage model. Compounds with a methyl or a methoxy group in the para position of the benzene ring were very potent in both assays. The results are discussed on the basis of the proposed model for the binding of this class of inhibitors to HLE and a possible mechanism of inhibition is presented.
authors.affiliation: Department of Medicinal Chemical Research, Merck Research Laboratories, Rahway, New Jersey 07065.
authors.forename: S K
authors.initials: SK
authors.lastname: Shah
authors.forename: C P
authors.initials: CP
authors.lastname: Dorn
authors.forename: P E
authors.initials: PE
authors.lastname: Finke
authors.forename: J J
authors.initials: JJ
authors.lastname: Hale
authors.forename: W K
authors.initials: WK
authors.lastname: Hagmann
authors.forename: K A
authors.initials: KA
authors.lastname: Brause
authors.forename: G O
authors.initials: GO
authors.lastname: Chandler
authors.forename: A L
authors.initials: AL
authors.lastname: Kissinger
authors.forename: B M
authors.initials: BM
authors.lastname: Ashe
authors.forename: H
authors.initials: H
authors.lastname: Weston
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D006801:Humans; D006868:Hydrolysis; D019272:Leukocyte Elastase; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D014961:X-Ray Diffraction; D047090:beta-Lactams / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001384:Azetidines; D047090:beta-Lactams; C077561:4-((4-carboxyphenyl)oxy)-3,3-diethyl-1-(((phenylmethyl)amino)carbonyl)-2-azetidinone; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase