title: Orally active beta-lactam inhibitors of human leukocyte elastase. 3. Stereospecific synthesis and structure-activity relationships for 3,3-dialkylazetidin-2-ones.
abstract: The stereospecific synthesis of several 4-[(4-carboxyphenyl)oxy]- 3,3-dialkyl-1-[[(1-phenylalkyl)-amino]carbonyl]azetidin-2-on es 3 is described in which the C-3 alkyl groups were varied from methyl to butyl as well as allyl, benzyl and methoxymethyl. The structure-activity relations for these compounds are discussed in terms of the hydrolytic stability of the beta-lactam ring, their in vitro inhibitory potency for human leukocyte elastase (HLE), and their in vivo oral efficacy in an HLE-mediated hamster lung hemorrhage assay. Further alkyl substitution on the benzylic urea moiety, especially in the R configuration, afforded enhanced HLE inhibition and in vivo efficacy. The stereochemical assignments for (3R,4S)-4-[(4-carboxyphenyl)oxy]-3-ethyl-3-methyl-1-[[((R)-1- phenylpropyl)amino]carbonyl]azetidin-2-one (42a) (kobs/[I] = 91,000 M-1 s-1) were confirmed with an X-ray structure determination, which was also utilized to develop an HLE inhibition model.
authors.affiliation: Department of Medicinal Chemical Research, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
authors.forename: P E
authors.initials: PE
authors.lastname: Finke
authors.forename: S K
authors.initials: SK
authors.lastname: Shah
authors.forename: D S
authors.initials: DS
authors.lastname: Fletcher
authors.forename: B M
authors.initials: BM
authors.lastname: Ashe
authors.forename: K A
authors.initials: KA
authors.lastname: Brause
authors.forename: G O
authors.initials: GO
authors.lastname: Chandler
authors.forename: P S
authors.initials: PS
authors.lastname: Dellea
authors.forename: K M
authors.initials: KM
authors.lastname: Hand
authors.forename: A L
authors.initials: AL
authors.lastname: Maycock
authors.forename: D G
authors.initials: DG
authors.lastname: Osinga
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D019272:Leukocyte Elastase; D009682:Magnetic Resonance Spectroscopy; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001384:Azetidines; D047090:beta-Lactams; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase